JP7385356B2 - Divalent bromodomain inhibitors and their uses - Google Patents

Description

Related Applications This application is filed under 35 USC § 119(e) under USSN 62/259,797, filed November 25, 2015, USSN 62/261,703, filed December 1, 2016, and USSN 62/338,968, filed May 19, 1995, each of which is incorporated herein by reference.

GOVERNMENT SUPPORT This invention was made with government support under Grant No. U01 HD076508 awarded by the National Institutes of Health. The Government has certain rights in this invention.

BACKGROUND OF THE INVENTION Cell-cell interactions and signal transduction often depend on multivalent interactions between receptors and their corresponding ligands (see, for example, Mammen et al. Angewandte Chemie International Edition 1998, 37 , 2754-2794). As is often the case with the binding of carbohydrates (e.g. glycoproteins, glycolipids, polysaccharides, or proteoglycans) to lectins that have several binding sites, individual weak interactions may result in avidity effects. (see, for example, Monsigny et al. Carbohydrate letters 2000, 4, 35-52) through multivalent interactions, a phenomenon known as the avidity effect. Multivalent ligands with either homo- or hetero-binding motifs can interact with oligomeric receptors, oligomerize monomeric receptors, or bind the effective molarity of the ligand. Binding activity is exhibited by several mechanisms, such as an increase in the binding activity (see, for example, Kiessling et al. Current opinion in chemical biology 2000, 4, 696-703). Furthermore, multivalent ligands can exhibit long residence times (see, for example, Illendula et al. Science 2015, 347, 779-784). These historical observations from nature establish a strong rationale for the discovery of multivalent ligands (see, for example, Profit, et al. Journal of the American Chemical Society 1999, 121, 280- 283).

Molecular recognition of chromatin by transcriptional or epigenetic complexes is often mediated by proteins with single or multiple "reader" domains, which at specific stages of post-translational modification include histone proteins, DNA, or bind to transcription factors. In the context of transcriptional activation, recruitment of histone acetyltransferases results in N-acetylation (Kac) of lysine residues on histone proteins and transcription factors. Following this, local hyperacetylation leads to the recruitment of coactivator proteins with acetyl-lysine recognition domains, or bromodomains. Bromodomains are bundles of antiparallel alpha helices that recognize mono- or di-acetylated peptides through a hydrophobic pocket with adjacent conserved asparagine residues (e.g., Filippakopoulos, P. & Knapp, S. Nature reviews. Drug discovery 2014, 13, 337-356). Human bromodomains of the BET (bromodomains and extra-terminal domains) family are transcriptional coactivators involved in cell cycle progression, transcriptional activation, and elongation (e.g., Zeng, L. & Zhou, M. M. FEBS letters 2002, 513, 124-128; Smith, S. G. & Zhou, M. M. ACS Chem Biol 2015, doi:10.1021/acschembio.5b00831). BET bromodomains (BRD2, BRD3, BRD4 and BRDT) are critical for chromatin-dependent signaling from master regulatory transcription factors to RNA polymerase II. It is a mediator. BRD4 has emerged as a therapeutic target in cancer, particularly as a coactivator protein for the common oncoprotein MYC (see, for example, Zuber, J. et al. Nature 2011, 478, 524-528; Delmore, J. E. et al. Cell 2011, 146, 904-917). Furthermore, BRD4 promotes transcription elongation through recruitment or activation of positive transcription elongation factors (P-TEFb) and displacement of negative regulators (HEXIM1 and 7SK snRNAs) (e.g., Yang , Z. et al. Molecular cell 2005, 19, 535-545; Krueger et al. PloS one 2010, 5, e12335).

In recent years, compounds that are bromodomain binding agents have been published in international PCT publications WO 2015/013635, WO 2015/117083, WO 2015/117055, WO 2015/117053, WO 2015/117087, WO 2014/ 159392, WO 2014/195951, WO 2012/075383, WO 2011/054553, WO 2011/054841, WO 2011/054844, WO 2011/054845, WO 2011/054846, WO 2011/054848, WO 2011/143669, and WO 2011 /161031, each of which is incorporated herein by reference. Additionally, Japanese patent application publication JP 2008/156311 (incorporated herein by reference) describes BRD2 bromodomain binding agents useful for treating viral infections and inhibiting viral replication. Disclosed are benzimidazole derivatives that have been found. International PCT publication WO 2009/084693 (incorporated herein by reference) describes a series of thienotypic compounds that inhibit the binding between acetylated histones and bromodomain-containing proteins, which are useful as anticancer agents. Triazolodiazepine derivatives are disclosed. International PCT Publication WO 2011/054843 (incorporated herein by reference) states that compounds that inhibit the binding of bromodomains to their cognate acetylated proteins may be used in autoimmune and inflammatory diseases. It is suggested that it may be useful for the treatment of.

The first direct-acting bromodomain antagonist, JQ1, was reported in 2010 (Figure 1a) (see, for example, Filippakopoulos et al. Nature 2010, 468, 1067-1073; WO (see 2011/143669). JQ1 is a potent and BET-selective thieno-1,4-diazepine that binds to critical asparagine through a methyl-thiazolo moiety. JQ1 has proven to be a valuable chemical probe for mechanistic and translational research, providing validation of pharmacological targets in predictive models of solid tumors and hematological diseases. ing. The structure of JQ1 is as follows:
It is as follows.

More recently, an isoxazole BET inhibitor, I-BET151, has been reported (see, for example, Dawson, MA et al. Nature 2011, 478, 529-533). I-BET151 exhibits comparable performance to JQ1 in biochemical and cellular assays (see, for example, FIG. 6). The structure of I-BET151 is as follows:
It is as follows.

Already, more than eight BRD4 antagonists have advanced into human clinical studies as cancer treatments (see, for example, Tanaka, M. et al. Pharmaceutical patent analyst 2015, 4, 261-284). All BRD4 antagonists established to date are monovalent inhibitors that interact with either bromodomain 1 (BD1) or bromodomain 2 (BD2) in a selective or non-selective manner. The significance of tandem BET bromodomains has not been resolved mechanistically (see, for example, Schroder et al. The Journal of biological chemistry 2012, 287, 1090-1099). Although chromatin binding is mostly influenced by BD1 (see, for example, Baud, M. G. et al. Science 2014, 346, 638-641), genetic and biochemical studies have shown that both domains play a role in transcriptional activation. (See, for example, Picaud et al. Proc Natl Acad Sci U S A 2013, 110, 19754-19759, doi:10.1073/pnas.1310658110). Despite advances in this area, there remains a need for additional strong and safe bromodomain binders. Given that bromodomain-containing proteins contain more than one ligand binding site of interest, multivalent ligands that target bromodomain-containing proteins have great potential therapeutic value.

SUMMARY OF THE INVENTION Gene regulation is fundamentally governed by a collection of reversible, non-covalent bonds of macromolecules. Signal transduction to RNA polymerase requires higher order protein complexes that are spatially regulated by assembly factors that can read the steps of post-translational modification of chromatin. Epigenetic readers are structurally diverse proteins, and each epigenetic leader has one or more evolutionarily conserved proteins that recognize covalent modifications of proteins (e.g., histones) or DNA. It has effector modules. ε-N-acetylation (Kac) of lysine residues on histone tails is associated with open chromatin architecture and transcriptional activation. Context-specific molecular recognition of acetyl-lysine is primarily mediated by bromodomains.

Bromodomain-containing proteins are components of transcription factor complexes such as TBP (TATA box-binding protein)-associated factor 1 (TAF1), CREB-binding protein (CBP or CREBBP), P300/CBP-associated factor (PCAF), and Gcn5) and as a determinant of epigenetic memory, it is of great biological interest. There are 41 human proteins containing a total of 57 different bromodomains. Despite large sequence variations, all bromodomains consist of four left-handed alpha helices (α _Z , α _A , α _B , and α _C ) share a conserved fold. Cocrystal structures with peptide substrates show that acetyl-lysine is recognized by a central hydrophobic cavity and anchored by hydrogen bonds with asparagine residues present in most bromodomains. It was shown that The bromo and extra terminal (BET) family (e.g. BRD2, BRD3, BRD4 and BRDT) is more divergent with two N-terminal bromodomains exhibiting a high degree of sequence conservation. They share a common domain architecture, including a C-terminal recruitment domain.

Recent studies have established a compelling rationale for targeting BRD4 in cancer. BRD4 functions to promote cell cycle progression, and knockdown in cultured cancer cell lines promotes G1 phase arrest. BRD4 is an important mediator of transcription elongation and functions to recruit the positive transcription elongation factor complex (P-TEFb). Cyclin-dependent kinase 9, a core component of P-TEFb, is a well-established target in chronic lymphocytic leukemia and has recently been linked to c-Myc-dependent transcription. The bromodomain present in BRD4 recruits P-TEFb to mitotic chromosomes, resulting in increased expression of growth-promoting genes. It has been found that BRD4 remains bound to transcription start sites of expressed genes throughout the M/G1 phase, but is absent from start sites expressed later in the cell cycle. Knockdown of BRD4 in proliferating cells has been shown to lead to G1 phase arrest and apoptosis by reducing the expression levels of genes important for mitotic progression and survival.

Importantly, BRD4 was recently identified as a component of a recurrent t(15;19) chromosomal translocation in an aggressive form of human squamous cell carcinoma. Such a translocation causes the tandem N-terminal bromodomain of BRD4 to be expressed as an in-frame chimera with the nuclear protein in testis (NUT) protein. This genetically defines NUT midline carcinoma (NMC). Functional studies in patient-derived NMC cell lines confirmed the essential role of the BRD4-NUT oncoprotein in maintaining the proliferative advantage and differentiation block characteristic of this malignancy. Notably, RNA silencing of BRD4-NUT gene expression arrests proliferation and promotes squamous differentiation with a marked increase in cytokeratin expression. Bromodomains may also downregulate Myc and other transcription factors such as interleukin 7 receptor (IL7R). These observations highlight the utility and therapeutic potential of binders or inhibitors of bromodomain-containing proteins.

Some bromodomain-containing proteins (eg, BRD4) have a tandem bromodomain primary structure that includes more than one bromodomain (eg, BRD4 includes BD1 and BD2). The invention relates, in part, to bivalent inhibitors of BET bromodomains that target bromodomain-containing proteins through multivalent interactions. The bivalent inhibitors provided herein are particularly potent inhibitors of BET bromodomains and, therefore, can be used to treat diseases or conditions associated with bromodomain-containing proteins.

In one aspect, the present invention provides compounds represented by formulas (I), (II), (III), (IV), (V), and (VI). The compounds described herein are binders of transcription factors, such as bromodomain-containing proteins (eg, BET proteins). The compounds are useful in male contraception and in a wide range of diseases, including diseases associated with bromodomains, diseases associated with bromodomain activity (e.g., aberrant activity), diseases associated with bromodomain-containing proteins, and diseases associated with bromodomain-containing proteins; It may be useful in treating and/or preventing diseases associated with domain-containing protein activity (eg, aberrant activity). Diseases that may be treated and/or prevented by the methods of the present disclosure include, but are not limited to, proliferative diseases (e.g., cancer, benign neoplasms, pathological angiogenesis, inflammatory diseases, and autoimmune diseases). ), cardiovascular diseases, viral infections, fibrotic diseases, neurological diseases, metabolic diseases, endocrine diseases, and radiation poisoning. Also provided in this disclosure are pharmaceutical compositions, kits, methods, and uses that include or use the compounds described herein.

In one aspect, the invention provides a homodimer comprising two monomers, where the two monomers are independently JQ-1 or an analog thereof (e.g., Filippakopoulos et al. Nature 2010, 468, 1067-1073; see WO 2011/143669). In certain embodiments, the monomers (i.e., JQ-1 or an analog thereof) are linked through the 2 and 6 positions of the monomer (referred to herein as a (2+6) homodimer). ). For example, in one aspect, the invention provides formula (I):
and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof where L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and m are as described herein.

In certain embodiments, the JQ-1 or JQ-1-like monomers are linked through the 6-position of the monomer (referred to herein as a (6+6) homodimer). For example, in another aspect, the invention provides formula (II):
and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof where L, R ¹ , R ² , R ³ , R ⁴ , and m are as described herein.

In certain embodiments, the JQ-1 or JQ-1-like monomers are linked through the 2-position of the monomer (referred to herein as a (2+2) homodimer). For example, in certain embodiments, the present invention provides formula (III):
Compounds represented by the formula where L, R ¹ , R ³ , R ⁴ , R ⁵ , and m are as described herein.

In another aspect, the invention provides a heterodimer comprising two monomers, where one monomer is JQ-1 or an analog thereof and the other monomer is , I-BET151 (see, for example, Dawson, MA et al. Nature 2011, 478, 529-533) or an analogue thereof. In certain embodiments, the monomers are attached through the 6-position of the JQ-1 or JQ-1-like monomer. For example, in certain embodiments, the present invention provides formula (IV):
and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof where L, R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , m, p, and q are as described herein It is as follows.

In certain embodiments, the heterodimers of the invention include monomers that are linked through the 2-position of a JQ-1 or JQ-1-like monomer. Therefore, in another aspect, the invention provides formula (V):
Compounds represented by the formula where L, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , m, p, and q are as described herein. .

The invention also provides homodimers comprising two monomers, where the monomers are I-BET151 or an analog thereof. For example, in another aspect, the invention provides formula (VI):
Compounds represented by the formula where L, R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , p, and q are as described herein.

The compounds provided herein are bivalent and therefore capable of simultaneously binding to two different sites on a single target (eg, a protein). For example, in any of the methods provided herein, a compound of the invention may simultaneously bind to two different sites on a bromodomain-containing protein. In certain embodiments, the compounds described herein bind to two different bromodomains of a bromodomain-containing protein simultaneously. For example, in certain embodiments, the compounds described herein bind simultaneously to bromodomain 1 (BD1) and bromodomain 2 (BD2) of a bromodomain-containing protein. In certain embodiments, compounds provided herein bind simultaneously to two different bromodomains of bromodomain-containing protein 4 (BRD4). In certain embodiments, the compounds provided herein bind to BD1 and BD2 of BRD2 simultaneously. In certain embodiments, compounds provided herein bind simultaneously to BD1 and BD2 of BRD3. In certain embodiments, compounds provided herein bind simultaneously to BD1 and BD2 of BRDT. In certain embodiments, compounds provided herein bind simultaneously to BD1 and BD2 of BRD4.

In yet another aspect, the present disclosure provides a compound described herein, such as a compound of formula (I), (II), (III), (IV), (V), or ( VI), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof), and optionally a pharmaceutical The present invention provides pharmaceutical compositions that include a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions described herein include a therapeutically or prophylactically effective amount of a compound described herein. Pharmaceutical compositions may be useful for treating and/or preventing disease in a subject in need thereof. The pharmaceutical composition also inhibits the replication of a virus, kills a virus, inhibits the activity of a bromodomain-containing protein, inhibits the activity of a bromodomain, inhibits the activity of a bromodomain-containing protein in a subject or a cell. Inhibiting the binding of bromodomains to acetylated lysine residues of histones or other proteins, modulating (e.g., inhibiting) transcriptional elongation, expression of genes regulated by bromodomain-containing proteins. It is also useful for modulating (eg, down-regulating or inhibiting) (eg, transcription), inducing apoptosis, and/or inducing G1 phase arrest. Good too.

In certain embodiments, a disease described herein is associated with activity (eg, abnormal activity, increased activity) of a bromodomain-containing protein. In certain embodiments, the disease is associated with function (eg, dysfunction) of bromodomain-containing proteins. In certain embodiments, the disease is associated with bromodomain activity (eg, abnormal activity, increased activity). In certain embodiments, the disease is associated with bromodomain function (eg, dysfunction).

In certain embodiments, the disease is a proliferative disease (e.g., cancer, benign neoplasm, pathological angiogenesis, inflammatory disease, or autoimmune disease), cardiovascular disease, viral infection, fibrotic disease, neurological disease. , metabolic disease, endocrine disease, or radiation poisoning.

Another aspect of the present disclosure relates to methods of treating the diseases described herein in a subject in need thereof. In certain embodiments, a method of treating a disease in a subject in need thereof comprises administering to the subject a compound provided herein, or a salt thereof, or a pharmaceutical composition thereof.

In another aspect, the disclosure provides methods for preventing the diseases described herein in a subject in need thereof. In certain embodiments, the method includes administering to a subject a compound provided herein, or a salt thereof, or a pharmaceutical composition.

Another aspect of the present disclosure relates to a method of reducing the risk of developing a disease in a subject in need thereof. The disease can be any disease described herein. In certain embodiments, the method comprises administering to a subject a compound provided herein, or a salt thereof, or a pharmaceutical composition thereof.

Another aspect of the present disclosure is that a virus, e.g. The present invention relates to a method of inhibiting the replication of HIV, human papillomavirus (HPV), hepatitis C virus (HCV), herpes simplex virus (HSV), Ebola virus, and influenza virus.

Another aspect of the present disclosure provides that viruses (e.g., human The present invention relates to a method for killing immunodeficiency virus (HIV), human papillomavirus (HPV), hepatitis C virus (HCV), herpes simplex virus (HSV), Ebola virus, and influenza virus).

In another aspect, the disclosure provides a method of inhibiting the activity of a bromodomain-containing protein in a subject or cell. In certain embodiments, the activity of the bromodomain-containing protein is an abnormal or unwanted activity (eg, increased activity) of the bromodomain-containing protein. In certain embodiments, the activity of a bromodomain-containing protein is selectively inhibited by the method (eg, when compared to the activity of a different kinase than the bromodomain-containing protein). In certain embodiments, the method comprises administering to a subject a compound described herein, or a salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the method includes contacting a cell with a compound described herein, or a salt thereof, or a pharmaceutical composition thereof.

In yet another aspect, the disclosure provides a method of inhibiting bromodomain activity in a subject or biological sample. In certain embodiments, the activity of the bromodomain that is inhibited is an abnormal or unwanted activity (eg, increased activity) of the bromodomain. In certain embodiments, the method comprises administering to a subject a compound described herein, or a salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the method includes contacting a biological sample with a compound described herein, or a salt thereof, or a pharmaceutical composition thereof.

In yet another aspect, the disclosure provides a method of inhibiting binding of a bromodomain to an acetylated lysine residue of a second protein (eg, a histone) in a subject or biological sample. In certain embodiments, the second protein is a protein that includes at least one acetylated lysine residue. In certain embodiments, the method comprises administering to a subject a compound described herein, or a salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the method includes contacting a biological sample with a compound described herein, or a salt thereof, or a pharmaceutical composition thereof.

In yet another aspect, the disclosure provides a method of modulating the expression (eg, transcription) of a gene regulated by a bromodomain-containing protein in a subject or biological sample. In certain embodiments, the method of modulating the expression (eg, transcription) of a gene is a method of downregulating or inhibiting the expression (eg, transcription) of the gene. The method may result in reduced levels of the gene product (eg, RNA, protein) in the cell. In certain embodiments, the method comprises administering to a subject a compound described herein, or a salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the method includes contacting a biological sample with a compound described herein, or a salt thereof, or a pharmaceutical composition thereof.

In yet another aspect, the present disclosure provides a method of modulating (eg, inhibiting) transcriptional elongation in a cell or biological sample of a subject, wherein the method comprises a compound provided herein. , or a salt thereof, or a pharmaceutical composition thereof, to a subject, or contacting a biological sample with a compound described herein, or a salt thereof, or a pharmaceutical composition thereof.

Another aspect of the present disclosure relates to a method of inducing apoptosis (e.g., apoptosis of cancer cells) in a subject cell or biological sample, the method comprising: a compound provided herein, or a salt thereof; or a pharmaceutical composition thereof to a subject, or contacting a biological sample with a compound described herein, or a salt thereof, or a pharmaceutical composition thereof.

Another aspect of the present disclosure relates to a method for inducing G1 phase arrest in a cell or biological sample of a subject, the method comprising using a compound provided herein, or a salt thereof, or a pharmaceutical composition thereof. The method includes administering to a subject or contacting a biological sample with a compound described herein, or a salt thereof, or a pharmaceutical composition thereof.

Methods of the present disclosure may include administering to a subject an effective amount of a compound or pharmaceutical composition described herein. Methods of the present disclosure may also include contacting a biological sample (eg, a cell) with an effective amount of a compound or pharmaceutical composition described herein. The methods of the present disclosure may also include contacting a virus-infected cell with an effective amount of a compound or pharmaceutical composition described herein. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the methods of the present disclosure further include administering to the subject an additional pharmaceutical agent in combination with a compound or pharmaceutical composition described herein. In certain embodiments, the methods of the present disclosure further include contacting the biological sample (eg, cells) with an additional pharmaceutical agent in combination with a compound or pharmaceutical composition described herein. In certain embodiments, the methods of the present disclosure further include contacting the virus with an additional pharmaceutical agent in combination with a compound or pharmaceutical composition described herein. In certain embodiments, the combination of an additional pharmaceutical agent and a compound or pharmaceutical composition described herein is synergistic.

Another aspect of the present disclosure relates to methods of screening libraries of compounds to identify compounds that are useful in the methods of the present disclosure.

Another aspect of the present disclosure relates to a kit comprising a container with a compound or pharmaceutical composition described herein. The kits described herein may include a single dose or multiple doses of a compound or pharmaceutical composition described herein. The kits provided may be useful in the methods of this disclosure. In certain embodiments, the kit further includes instructions for using the kit.

In yet another aspect, the disclosure provides compounds and pharmaceutical compositions described herein for use in the methods of the disclosure.

The invention also provides the use of the compounds and pharmaceutical compositions provided herein for the manufacture of a medicament for the treatment of the diseases discussed herein.

This application references various issued patents, published patent applications, scholarly articles, and other publications, all of which are incorporated herein by reference. The details of one or more aspects of the disclosure are set forth herein. Other features, objects, and advantages of the disclosure will be apparent from the detailed description, figures, examples, and claims.

Definitions Chemical Definitions Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of Elements on the inside cover of the CAS version, Handbook of Chemistry and Physics, 75th Ed., and specific functional groups are generally defined as described herein. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, can be found in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons , Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987. There is.

The compounds described herein may contain one or more asymmetric centers and therefore exist in different stereoisomeric forms, including enantiomers and/or diastereomers. Can be done. For example, the compounds described herein can be in the form of individual enantiomers, diastereomers, or geometric isomers, or can be stereoisomers, including racemic mixtures or mixtures enriched in one or more stereoisomers. It can be in the form of a body mixture. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and chiral salt formation and crystallization; or preferred isomers can be isolated by asymmetric synthesis. It can be prepared by For example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962) and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention additionally encompasses the compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

In the formula,
is a single bond where the stereochemistry of the moiety directly attached to it is unspecified;
is absent or a single bond, and
is a single bond or a double bond.

Unless otherwise specified, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the present structure can be used except when hydrogen is replaced by deuterium or tritium, when ¹⁹ F is replaced with ¹⁸ F, or when ¹² C is replaced with ¹³ C or ¹⁴ C. Compounds that have are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

When a range of values is recited, it is intended to cover each value and subrange within the range. For example, "C _1-6 alkyl" means C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _{2-5, C 2-4 ,} C _2-3 , C _3-6 , C _3-5 , C _3-4 , C _4-6 , C _4-5 , and It is intended to cover C _5-6 .

The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon radical having from 1 to 20 carbon atoms ("C _1-10 alkyl"). In some embodiments, alkyl groups have 1-9 carbon atoms ("C _1-9 alkyl"). In some embodiments, alkyl groups have 1-8 carbon atoms ("C _1-8 alkyl"). In some embodiments, alkyl groups have 1-7 carbon atoms ("C _1-7 alkyl"). In some embodiments, alkyl groups have 1-6 carbon atoms (“C _1-6 alkyl”). In some embodiments, alkyl groups have 1-5 carbon atoms ("C _1-5 alkyl"). In some embodiments, alkyl groups have 1-4 carbon atoms ("C _1-4 alkyl"). In some embodiments, alkyl groups have 1-3 carbon atoms ("C _1-3 alkyl"). In some embodiments, an alkyl group has 1-2 carbon atoms (“C _1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom ("C ₁ alkyl"). In some embodiments, alkyl groups have 2-6 carbon atoms (“C _2-6 alkyl”). Examples of C _1-6 alkyl groups are methyl (C ₁ ), ethyl (C ₂ ), propyl (C ₃ ) (for example n-propyl, isopropyl), butyl (C ₄ ) (for example n-butyl). , tert-butyl, sec-butyl, iso-butyl), pentyl (C ₅ ) (for example, n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl, and hexyl ( C ₆ ) (for example, n-hexyl). Additional examples of alkyl groups include n-heptyl (C ₇ ), n-octyl (C ₈ ), etc. Unless otherwise specified , each of the alkyl groups is independently unsubstituted (an "unsubstituted alkyl") or substituted with one or more substituents (for example, a halogen such as F) (a "substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C _1-10 alkyl (such as unsubstituted C _1-6 alkyl, such as -CH ₃ (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr , for example, unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, for example, unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is substituted C _1-10 alkyl ( Substituted C _1-6 alkyl, such as -CF ₃ , Bn).

The term "haloalkyl" is a substituted alkyl group in which one or more of the hydrogen atoms is independently replaced by halogen, such as fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1-8 carbon atoms (“C _1-8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1-6 carbon atoms (“C _1-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1-4 carbon atoms (“C _1-4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1-3 carbon atoms (“C _1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1-2 carbon atoms (“C _1-2 haloalkyl”). Examples of haloalkyl groups include -CF ₃ , -CF ₂ CF ₃ , -CF ₂ CF ₂ CF ₃ , -CCl ₃ , -CFCl ₂ , -CF ₂ Cl, and the like.

The term "heteroalkyl" refers to at least one heteroatom selected from oxygen, nitrogen, or sulfur (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 heteroatoms) atoms) within the parent chain (i.e. inserted between adjacent carbon atoms of the parent chain) and/or at one or more terminal position(s) of the parent chain. , further inclusive, refers to an alkyl group. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and one or more heteroatoms in the parent chain (“heteroC _1-10 alkyl”). In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 9 carbon atoms and one or more heteroatoms in the parent chain ("heteroC _1-9 alkyl"). In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("heteroC _1-8 alkyl"). In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 7 carbon atoms and one or more heteroatoms in the parent chain ("heteroC _1-7 alkyl"). In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC _1-6 alkyl"). In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC _1-5 alkyl"). In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC _1-4 alkyl"). In some embodiments, a heteroalkyl group refers to a saturated group having 1-3 carbon atoms and 1 heteroatom in the parent chain ("heteroC _1-3 alkyl"). In some embodiments, a heteroalkyl group refers to a saturated group having 1-2 carbon atoms and 1 heteroatom in the parent chain ("heteroC _1-2 alkyl"). In some embodiments, a heteroalkyl group refers to a saturated group having one carbon atom and one heteroatom in the parent chain (“heteroC ₁ alkyl”). In some embodiments, a heteroalkyl group refers to a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms in the parent chain (“heteroC _2-6 alkyl”). Unless otherwise specified, each heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). ). In certain embodiments, a heteroalkyl group is an unsubstituted heteroC _1-10 alkyl. In certain embodiments, a heteroalkyl group is a substituted heteroC _1-10 alkyl.

The term "alkenyl" refers to straight or branched chains having from 2 to 20 carbon atoms and one or more carbon-carbon double bonds (for example, 1, 2, 3, or 4 double bonds). Refers to the radical of a branch hydrocarbon group. In some embodiments, alkenyl groups have 2-9 carbon atoms (“C _2-9 alkenyl”). In some embodiments, alkenyl groups have 2-8 carbon atoms (“C _2-8 alkenyl”). In some embodiments, alkenyl groups have 2-7 carbon atoms (“C _2-7 alkenyl”). In some embodiments, alkenyl groups have 2-6 carbon atoms (“C _2-6 alkenyl”). In some embodiments, alkenyl groups have 2-5 carbon atoms (“C _2-5 alkenyl”). In some embodiments, alkenyl groups have 2-4 carbon atoms (“C _2-4 alkenyl”). In some embodiments, alkenyl groups have 2-3 carbon atoms (“C _2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C ₂ alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C _2-4 alkenyl groups are ethenyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl ( C ₄ ), etc. Examples of C _2-6 alkenyl groups include the aforementioned C _2-4 alkenyl groups as well as pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ), and the like. Additional examples of alkenyl groups include heptenyl ( _C7 ), octenyl ( _C8 ), octatrienyl ( _C8 ), and the like. Unless otherwise specified, each alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents (a "substituted alkenyl"). . In certain embodiments, an alkenyl group is an unsubstituted C _2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted C _2-10 alkenyl. In an alkenyl group, a C=C double bond of unspecified stereochemistry (for example, -CH=CHCH _or
may be an (E)- or (Z)-double bond.

The term "heteroalkenyl" refers to at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within the parent chain (i.e., Refers to an alkenyl group that is inserted between adjacent carbon atoms of the parent chain) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain (“heteroC _2-10 alkenyl ”). In some embodiments, a heteroalkenyl group refers to a group having 2 to 9 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain (“heteroC _2-9 alkenyl”). In some embodiments, a heteroalkenyl group refers to a group having 2 to 8 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain (“heteroC _2-8 alkenyl”). In some embodiments, a heteroalkenyl group refers to a group having 2 to 7 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain (“heteroC _2-7 alkenyl”). In some embodiments, a heteroalkenyl group refers to a group having 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain (“heteroC _2-6 alkenyl”). In some embodiments, a heteroalkenyl group refers to a group having 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain (“heteroC _{2- 5-} alkenyl”). In some embodiments, a heteroalkenyl group refers to a group having 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain (“heteroC _{2- 4-} alkenyl”). In some embodiments, a heteroalkenyl group refers to a group having 2-3 carbon atoms, at least one double bond, and one heteroatom in the parent chain (“heteroC _2-3 alkenyl ”). In some embodiments, a heteroalkenyl group refers to a group having 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain (“heteroC _{2- 6} alkenyl”). Unless otherwise specified, each heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted with one or more substituents (a "substituted heteroalkenyl"). ). In certain embodiments, a heteroalkenyl group is an unsubstituted hetero _C2-10 alkenyl. In certain embodiments, a heteroalkenyl group is a substituted hetero C _2-10 alkenyl.

The term "alkynyl" refers to straight or branched carbonized carbon atoms having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (for example, 1, 2, 3, or 4 triple bonds). Refers to a radical of a hydrogen group (“C _2-10 alkynyl”). In some embodiments, alkynyl groups have 2-9 carbon atoms (“C _2-9 alkynyl”). In some embodiments, alkynyl groups have 2-8 carbon atoms (“C _2-8 alkynyl”). In some embodiments, alkynyl groups have 2-7 carbon atoms (“C _2-7 alkynyl”). In some embodiments, alkynyl groups have 2-6 carbon atoms (“C _2-6 alkynyl”). In some embodiments, alkynyl groups have 2-5 carbon atoms (“C _2-5 alkynyl”). In some embodiments, alkynyl groups have 2-4 carbon atoms (“C _2-4 alkynyl”). In some embodiments, alkynyl groups have 2-3 carbon atoms (“C _2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C ₂ alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C _2-4 alkynyl groups include, without limitation, ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), 2-butynyl (C ₄ ) etc. Examples of C _2-6 alkenyl groups include the aforementioned C _2-4 alkynyl groups as well as pentynyl (C ₅ ), hexynyl (C ₆ ), and the like. Additional examples of alkynyl groups include heptynyl ( _C7 ), octynyl ( _C8 ), and the like. Unless otherwise specified, each alkynyl group is independently unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"). . In certain embodiments, an alkynyl group is an unsubstituted C _2-10 alkynyl. In certain embodiments, an alkynyl group is a substituted C _2-10 alkynyl.

The term "heteroalkynyl" refers to at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within the parent chain (i.e., Refers to an alkynyl group inserted between adjacent carbon atoms of the parent chain) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain (“heteroC _2-10 alkynyl”) ). In some embodiments, a heteroalkynyl group refers to a group having 2 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain (“heteroC _2-9 alkynyl ”). In some embodiments, a heteroalkynyl group refers to a group having 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain (“heteroC _2-8 alkynyl ”). In some embodiments, a heteroalkynyl group refers to a group having 2 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain (“heteroC _2-7 alkynyl ”). In some embodiments, a heteroalkynyl group refers to a group having 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain (“heteroC _2-6 alkynyl ”). In some embodiments, a heteroalkynyl group refers to a group having 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain (“heteroC _2-5 Alkynyl). In some embodiments, a heteroalkynyl group refers to a group having 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain (“heteroC _2-4 Alkynyl). In some embodiments, a heteroalkynyl group refers to a group having 2 to 3 carbon atoms, at least one triple bond, and one heteroatom in the parent chain (“heteroC _2-3 alkynyl”) ). In some embodiments, a heteroalkynyl group refers to a group having 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain (“heteroC _2-6 Alkynyl). Unless otherwise specified, each heteroalkynyl group is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted with one or more substituents ("substituted heteroalkynyl"). ). In certain embodiments, a heteroalkynyl group is an unsubstituted hetero C _2-10 alkynyl. In certain embodiments, a heteroalkynyl group is a substituted hetero C _2-10 alkynyl.

The term "carbocyclyl" or "carbocycle" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms and 0 heteroatoms in the non-aromatic ring system (" C _3-14 carbocyclyl). In some embodiments, carbocyclyl groups have 3-10 ring carbon atoms (“C _3-10 carbocyclyl”). In some embodiments, carbocyclyl groups have 3 to 8 ring carbon atoms (“C _3-8 carbocyclyl”). In some embodiments, carbocyclyl groups have 3 to 7 ring carbon atoms (“C _3-7 carbocyclyl”). In some embodiments, carbocyclyl groups have 3 to 6 ring carbon atoms (“C _3-6 carbocyclyl”). In some embodiments, carbocyclyl groups have 4 to 6 ring carbon atoms (“C _4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5-6 ring carbon atoms (“C _5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5-10 ring carbon atoms (“C _5-10 carbocyclyl”). Exemplary C _3-6 carbocyclyl groups include, without limitation, cyclopropyl (C ₃ ), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl (C ₅ ), cyclopentenyl ( C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), and the like. Exemplary C _3-8 carbocyclyl groups include, without limitation, the aforementioned C _3-6 carbocyclyl groups as well as cycloheptyl (C ₇ ), cycloheptenyl (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), cyclooctyl (C ₈ ), cyclooctenyl (C ₈ ), bicyclo[2.2.1]heptanyl (C ₇ ), bicyclo[2.2.2]octanyl (C ₈ ), and the like. Exemplary C _3-10 carbocyclyl groups include, without limitation, the aforementioned C _3-8 carbocyclyl groups as well as cyclononyl (C ₉ ), cyclononenyl (C ₉ ), cyclodecyl (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro- Includes 1H-indenyl (C ₉ ), decahydronaphthalenyl (C ₁₀ ), spiro[4.5]decanyl (C ₁₀ ), and the like. As the foregoing examples illustrate, in some embodiments, carbocyclyl groups are monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., bicyclic ("bicyclic carbocyclyl") or tricyclic). (containing fused, bridged or spiro ring systems, such as a "tricyclic carbocyclyl") and may be saturated or have one or more carbon-carbon double or triple bonds. may contain bonds. "Carbocyclyl" also includes ring systems in which a carbocycle is fused to one or more aryl or heteroaryl groups, as defined above, where the point of attachment is on the carbocycle. Even in such a case, the number of carbon atoms in the carbon ring system continues to be specified. Unless otherwise specified, each carbocyclic group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). ). In certain embodiments, the carbocyclyl group is an unsubstituted C _3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C _3-14 carbocyclyl.

In some embodiments, "carbocyclyl" is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C _3-14 cycloalkyl"). In some embodiments, cycloalkyl groups have 3 to 10 ring carbon atoms (“C _3-10 cycloalkyl”). In some embodiments, cycloalkyl groups have 3 to 8 ring carbon atoms (“C _3-8 cycloalkyl”). In some embodiments, cycloalkyl groups have 3 to 6 ring carbon atoms (“C _3-6 cycloalkyl”). In some embodiments, cycloalkyl groups have 4 to 6 ring carbon atoms (“C _4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5-6 ring carbon atoms (“C _5-6 cycloalkyl”). In some embodiments, cycloalkyl groups have 5-10 ring carbon atoms ("C _5-10 cycloalkyl"). Examples of C _5-6 cycloalkyl groups include cyclopentyl (C ₅ ), cyclohexyl (C ₅ ). Examples of C _3-6 cycloalkyl groups include the aforementioned C _5-6 cycloalkyl groups as well as cyclopropyl (C ₃ ) and cyclobutyl (C ₄ ). Examples of C _3-8 cycloalkyl groups include the aforementioned C _3-6 cycloalkyl groups as well as cycloheptyl (C ₇ ) and cyclooctyl (C ₈ ). Unless otherwise specified, each cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). . In certain embodiments, a cycloalkyl group is an unsubstituted C _3-14 cycloalkyl. In certain embodiments, a cycloalkyl group is a substituted C _3-14 cycloalkyl.

The term "heterocyclyl" or "heterocycle" refers to a 3- to 14-membered non-aromatic ring system radical having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently (3- to 14-membered heterocyclyl) selected from nitrogen, oxygen, and sulfur. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, as valency permits. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl") or polycyclic (for example, fused, such as bicyclic ("bicyclic heterocyclyl") or tricyclic ("tricyclic heterocyclyl") systems). (ring systems, bridged ring systems or spiro ring systems) and may be saturated or contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also refers to a ring system in which a heterocycle, as defined above, is fused to one or more carbocyclyl groups, where the point of attachment is either on the carbocycle or on the heterocycle, or Heterocycle also includes ring systems fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocycle, as defined above. Even in such a case, the number of ring members in the heterocyclic ring system is still designated as the number of ring members. Unless otherwise specified, each heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 14-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 14-membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, where each heteroatom is independently a nitrogen , oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, where each heteroatom is independently a nitrogen , oxygen, and sulfur (“5- to 8-membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, where each heteroatom is independently a nitrogen , oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary three-membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. includes. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl, and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl. , decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, Indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H -Furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3 -dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl , 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1 , 6-naphthyridinyl and the like.

The term "aryl" refers to monocyclic or polycyclic (e.g., bicyclic or tricyclic) having from 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. (“C _6-14 aryl”) refers to a radical of a 4n+2 aromatic ring system (eg, having 6, 10, or 14 π electrons shared in a cyclic array). In some embodiments, the aryl group has 6 ring carbon atoms (“C ₆ aryl”; eg, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C ₁₀ aryl”; eg, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C ₁₄ aryl”; eg, anthracyl). "Aryl" also includes ring systems in which the aryl ring is fused to one or more carbocyclyl or heterocyclyl groups, as defined above, where the radical or point of attachment is on the aryl ring. Even in such cases, the number of carbon atoms in the aryl ring system continues to be specified. Unless otherwise specified, each aryl group is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is an unsubstituted C _6-14 aryl. In certain embodiments, the aryl group is a substituted C _6-14 aryl.

The term "heteroaryl" refers to a 5- to 14-membered monocyclic or polycyclic (e.g. , bicyclic, tricyclic), a 4n+2 aromatic ring system (with, for example, 6, 10 or 14 π electrons shared in the cyclic arrangement), where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring is fused to one or more carbocyclyl or heterocyclyl groups, as defined above, where the point of attachment is on the heteroaryl ring. Even in such a case, the number of ring members in the heteroaryl ring system is still designated as the number of ring members. "Heteroaryl" also means a ring system in which a heteroaryl ring is fused to one or more aryl groups, as defined above, where the point of attachment is either on the aryl ring or on the heteroaryl ring. It also includes. Even in such a case, the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system is subsequently specified. In polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e. in a ring containing a heteroatom (e.g. (eg, 2-indolyl) or a ring containing no heteroatoms (eg, 5-indolyl).

In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each Heteroatoms are independently selected from nitrogen, oxygen, and sulfur (5-10 membered heteroaryl). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each Heteroatoms are independently selected from nitrogen, oxygen, and sulfur (5-8 membered heteroaryl). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each Heteroatoms are independently selected from nitrogen, oxygen, and sulfur (5-6 membered heteroaryl). In some embodiments, a 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each heteroaryl group is independently unsubstituted (an "unsubstituted heteroaryl") or substituted with one or more substituents (a "substituted heteroaryl"). ). In certain embodiments, a heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl. Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary six-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxane. Includes benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

"Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted with an aryl group, where the point of attachment is on the alkyl moiety (ie, -alkyl-aryl). In certain embodiments, aralkyl is -C _1-10 alkyl-aryl. In certain embodiments, aralkyl is -C _1-6 alkyl-aryl. In certain embodiments, aralkyl is -C _1-3 alkyl-aryl. In certain embodiments, aralkyl is -CH ₂ CH ₂ -aryl. In certain embodiments, aralkyl is _-CH2 -aryl. In certain embodiments, aralkyl is -alkyl-C _6-14 aryl. In certain embodiments, aralkyl is -alkyl-C ₆ aryl. In certain embodiments, aralkyl is -C _1-10 alkyl-C ₆ aryl. In certain embodiments, aralkyl is -C _1-6 alkyl-C ₆ aryl. In certain embodiments, aralkyl is -C _1-3 alkyl-C ₆ aryl. For example, in some embodiments, aralkyl is -CH ₂ CH ₂ -C ₆ aryl. In certain embodiments, aralkyl is _-CH2 - _C6aryl (eg, _-CH2 -phenyl).

"Heteroarylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted by a heteroaryl group, where the point of attachment is on the alkyl moiety (i.e., -alkyl-heteroaryl) . In certain embodiments, heteroarylalkyl is -C _1-10 alkyl-heteroaryl. In certain embodiments, heteroarylalkyl is -C _1-6 alkyl-heteroaryl. In certain embodiments, heteroarylalkyl is -C _1-3 alkyl-heteroaryl. In certain embodiments, heteroarylalkyl is _-CH2 -heteroaryl. In certain embodiments, heteroarylalkyl is -alkyl-heteroaryl, where the heteroaryl group is a 5-14 membered heteroaryl. In certain embodiments, heteroarylalkyl is -alkyl-heteroaryl, where the heteroaryl group is a 5-6 membered heteroaryl. In certain embodiments, heteroarylalkyl is -alkyl-heteroaryl, where the heteroaryl group is a 5-membered heteroaryl. In certain embodiments, heteroarylalkyl is -C _1-10 alkyl-heteroaryl, where the heteroaryl group is a 5-6 membered heteroaryl. In certain embodiments, heteroarylalkyl is -C _1-6 alkyl-heteroaryl, where the heteroaryl group is a 5-6 membered heteroaryl. In certain embodiments, heteroarylalkyl is -C _1-3 alkyl-heteroaryl, where the heteroaryl group is a 5-6 membered heteroaryl. In certain embodiments, heteroarylalkyl is _-CH2 -heteroaryl, where the heteroaryl group is a 5-6 membered heteroaryl.

"Carbocyclylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a carbocyclyl group, where the point of attachment is on the alkyl moiety (ie, -alkyl-carbocyclyl). In certain embodiments, carbocyclylalkyl is -C _1-10 alkyl-carbocyclyl. In certain embodiments, carbocyclylalkyl is -C _1-6 alkyl-carbocyclyl. In certain embodiments, carbocyclylalkyl is -C _1-3 alkyl-carbocyclyl. In certain embodiments, carbocyclylalkyl is _-CH2 -carbocyclyl. In certain embodiments, carbocyclylalkyl is -alkyl-C _3-14 carbocyclyl. In certain embodiments, carbocyclylalkyl is -alkyl-C _3-6 carbocyclyl. In certain embodiments, carbocyclylalkyl is -C _1-10 alkyl- _{C 3-6} carbocyclyl. In certain embodiments, carbocyclylalkyl is -C _1-6 alkyl- _{C 3-6} carbocyclyl. In certain embodiments, carbocyclylalkyl is -C _1-3 alkyl-C _3-6 carbocyclyl. In certain embodiments, carbocyclylalkyl is -CH ₂ -C _3-6 carbocyclyl.

"Heterocyclylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted with a carbocyclyl group, where the point of attachment is on the alkyl moiety (ie, -alkyl-heterocyclyl). In certain embodiments, heterocyclylalkyl is -C _1-10 alkyl-heterocyclyl. In certain embodiments, heterocyclylalkyl is -C _1-6 alkyl-heterocyclyl. In certain embodiments, heterocyclylalkyl is -C _1-3 alkyl-heterocyclyl. In certain embodiments, heterocyclylalkyl is -CH ₂ CH ₂ -heterocyclyl. In certain embodiments, heterocyclylalkyl is _-CH2 -heterocyclyl. In certain embodiments, heterocyclylalkyl is -alkyl-heterocyclyl, where the heterocyclyl group is 3-14 membered heterocyclyl. In certain embodiments, heterocyclylalkyl is -alkyl-heterocyclyl, where the heterocyclyl group is a 3- to 6-membered heterocyclyl. In certain embodiments, heterocyclylalkyl is -alkyl-heterocyclyl, where the heterocyclyl group is 5-10 membered heterocyclyl. In certain embodiments, heterocyclylalkyl is -alkyl-heterocyclyl, where the heterocyclyl group is 5-6 membered heterocyclyl. In certain embodiments, heterocyclylalkyl is -alkyl-heterocyclyl, where the heterocyclyl group is 5-membered heterocyclyl. In certain embodiments, heterocyclylalkyl is -C _1-10 alkyl-heterocyclyl, where the heterocyclyl group is 3-6 membered heterocyclyl. In certain embodiments, heterocyclylalkyl is -C _1-6 alkyl-heterocyclyl, where the heterocyclyl group is 3-6 membered heterocyclyl. In certain embodiments, heterocyclylalkyl is -C _1-3 alkyl-heterocyclyl, where the heterocyclyl group is 3-6 membered heterocyclyl. In certain embodiments, heterocyclylalkyl is -CH ₂ CH ₂ CH ₂ -heterocyclyl, where the heterocyclyl group is 3-6 membered heterocyclyl. In certain embodiments, heterocyclylalkyl is _-CH2 -heterocyclyl, where the heterocyclyl group is a 3- to 6-membered heterocyclyl.

The term "unsaturated bond" refers to a double or triple bond.

The term "unsaturated" or "partially unsaturated" refers to a moiety that includes at least one double or triple bond.

The term "saturated" refers to moieties that contain no double or triple bonds, ie, only single bonds.

Adding the suffix "-ene" to a group indicates that the group is a divalent moiety; for example, alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, Alkynylene is a divalent moiety of an alkynyl, heteroalkylene is a divalent moiety of a heteroalkyl, heteroalkenylene is a divalent moiety of a heteroalkenyl, and heteroalkynylene is a divalent moiety of a heteroalkynyl. , carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl. be.

Groups are optionally substituted unless explicitly specified otherwise. The term "optionally substituted" refers to substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. "Optionally substituted" refers to groups that may be substituted or unsubstituted (for example, "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl basis). In general, the term "substituted" refers to compounds in which at least one hydrogen present on a group is a permissible substituent, e.g. compounds stabilized by substitution (e.g. rearrangement). , by cyclization, elimination, or other reactions). Unless otherwise indicated, a "substituted" group has substituents at one or more substitutable positions on the group, and more than one position in any given structure is substituted. When , the substituents are either the same or different at each position. The term "substituted" is intended to encompass the substitution of organic compounds with all permissible substituents and includes any of the substituents described herein that results in the formation of a stable compound. Also includes. The present invention contemplates any and all such combinations to arrive at stable compounds. For the purposes of this invention, a heteroatom such as nitrogen may have a hydrogen substituent and/or any suitable substituent as described herein that satisfies the valency of the heteroatom. Good results in the formation of stable parts. The invention is in no way intended to be limited by the exemplary substitutions described herein.

Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^aa , -ON (R ^bb ) ₂ , -N(R ^bb ) ₂ , -N(R ^bb ) ₃ ⁺ X ^- , -N(OR ^cc )R ^bb , -SH, -SR ^aa , -SSR ^cc , -C(=O)R ^aa , -CO ₂ H, -CHO, -C(OR ^cc ) ₂ , -CO ₂ R ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , -OC(=O)N(R ^bb ) ₂ , -NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -C (=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -OC(=NR ^bb )N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , -OS(=O)R ^aa , - Si(R ^aa ) ₃ , -OSi(R ^aa ) ₃ C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=S)SR ^aa , -SC(=S) SR ^aa , -SC(=O)SR ^aa , -OC(=O)SR ^aa , -SC(=O)OR ^aa , -SC(=O)R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O)(OR ^cc ) ₂ , -OP(=O)(R ^aa ) ₂ , -OP(=O)(OR ^cc ) ₂ , -P(=O)(N(R ^bb ) ₂ ) ₂ , -OP(=O)(N(R ^bb ) ₂ ) ₂ , -NR ^bb P(=O)(R ^aa ) ₂ , -NR ^bb P(=O)(OR ^cc ) ₂ , -NR ^bb P(=O)(N(R ^bb ) ₂ ) ₂ , -P(R ^cc ) ₂ , -P(OR ^cc ) ₂ , -P(R ^cc ) ₃ ⁺ X ^- , -P(OR ^cc ) ₃ ⁺ X ⁻ , −P(R ^cc ) ₄ , −P(OR ^cc ) ₄ , −OP(R ^cc ) ₂ , −OP(R ^cc ) ₃ ⁺ X ⁻ , −OP(OR ^cc ) ₂ , −OP(OR ^{cc )} ₃ ^{+ _} _{_} ^_ _{_} ^_ _{_} ^_ _{_} ^{_ _} _{_ 10} alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, hetero C _1-10 alkyl, hetero C _2-10 alkenyl, hetero C _2-10 alkynyl, C _3-10 carbocyclyl, 3 ~14-membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is , independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups; where X ^- is a counterion;
Or the two geminal hydrogens on a carbon atom are the groups =O, =S, =NN(R ^bb ) ₂ , =NNR ^bb C(=O)R ^aa , =NNR ^bb C(=O)OR ^aa , = replaced with NNR ^bb S(=O) ₂ R ^aa , =NR ^bb , or =NOR ^cc ;
In each case, R ^aa is independently C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, hetero C _1-10 alkyl, hetero C _2-10 alkenyl, selected from hetero C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, or the two R ^aa groups are joined together. , forming a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently , substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;
R ^bb in any case is independently hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , - SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(= O)(R ^aa ) ₂ , -P(=O)(OR ^cc ) ₂ , -P(=O)(N(R ^cc ) ₂ ) ₂ , C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _{2-10 alkynyl, hetero C 1-10 alkyl, hetero C 2-10 alkenyl} , hetero C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5- to 14-membered heteroaryl, or the two R ^bb groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, Alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups; X ⁻ is a counterion;
In any case, R ^cc is independently hydrogen, C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, hetero C _1-10 alkyl, hetero C _2-10 alkenyl, hetero C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, or the two R ^cc groups are taken together to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently and is substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;
R ^dd in any case is independently halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^ee , -ON(R ^ff ) ₂ , - N(R ^ff ) ₂ , -N(R ^ff ) ₃ ⁺ X ^- , -N(OR ^ee )R ^ff , -SH, -SR ^ee , -SSR ^ee , -C(=O)R ^ee , -CO ₂ H, -CO ₂ R ^ee , -OC(=O)R ^ee , -OCO ₂ R ^ee , -C(=O)N(R ^ff ) ₂ , -OC(=O)N(R ^ff ) ₂ , - NR ^ff C(=O)R ^ee , -NR ^ff CO ₂ R ^ee , -NR ^ff C(=O)N(R ^ff ) ₂ , -C(=NR ^ff )OR ^ee , -OC(=NR ^ff ) R ^ee , -OC(=NR ^ff )OR ^ee , -C(=NR ^ff )N(R ^ff ) ₂ , -OC(=NR ^ff )N(R ^ff ) ₂ , -NR ^ff C(=NR ^ff ) N(R ^ff ) ₂ , -NR ^ff SO ₂ R ^ee , -SO ₂ N(R ^ff ) ₂ , -SO ₂ R ^ee , -SO ₂ OR ^ee , -OSO ₂ R ^ee , -S(=O)R ^ee , -Si(R ^ee ) ₃ , -OSi(R ^ee ) ₃ , -C(=S)N(R ^ff ) ₂ , -C(=O)SR ^ee , -C(=S)SR ^ee , - SC(=S)SR ^ee , -P(=O)(OR ^ee ) ₂ , -P(=O)(R ^ee ) ₂ , -OP(=O)(R ^ee ) ₂ , -OP(=O) (OR ^ee ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hetero C _1-6 alkyl, hetero C _2-6 alkenyl, hetero C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, Heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups, or two geminal R ^dd substituents joined together, = may form O or =S; where X ^- is a counterion;
In each case R ^ee is independently C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hetero C _1-6 alkyl, hetero C _2-6 alkenyl, selected from hetero C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl , heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups;
R ^ff in any case is independently hydrogen, C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hetero C _1-6 alkyl, hetero C _2-6 selected from alkenyl, hetero C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl, or two R ^ff groups are joined together. to form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are independently is substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups; and in each case R ^gg is independently halogen, -CN, -NO ₂ , -N ₃ , - SO ₂ H, -SO ₃ H, -OH, -OC _1-6 alkyl, -ON(C _1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₃ ⁺ X ^- , -NH ( _{C 1-6} alkyl) ₂ ⁺ X ^- , ^-NH ₂ (C _1-6 alkyl) ⁺ X ^- , -NH ₃ ⁺ C _1-6 alkyl), -N(OH)(C _1-6 alkyl), -NH(OH), -SH, -SC _1-6 alkyl, -SS(C _1-6 alkyl), -C(= O) (C _1-6 alkyl), -CO ₂ H, -CO ₂ (C _1-6 alkyl), -OC(=O) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl) , -C(=O)NH ₂ , -C(=O)N(C _1-6 alkyl) ₂ , -OC(=O)NH(C _1-6 alkyl), -NHC(=O)(C _{1 -6} alkyl), -N( _C1-6 alkyl)C(=O)( _C1-6 alkyl), _-NHCO2 ( _C1-6 alkyl), -NHC(=O)N( _C1-6 alkyl) ₂ , -NHC(=O)NH(C _1-6 alkyl), -NHC(=O)NH ₂ , -C(=NH)O(C _1-6 alkyl), -OC(=NH)( C _1-6 alkyl), -OC(=NH)OC _1-6 alkyl, -C(=NH)N(C _1-6 alkyl) ₂ , -C(=NH)NH(C _1-6 alkyl), -C(=NH)NH ₂ , -OC(=NH)N(C _1-6 alkyl) ₂ , -OC(NH)NH(C _1-6 alkyl), -OC(NH)NH ₂ , -NHC( NH)N(C _1-6 alkyl) ₂ , -NHC(=NH)NH ₂ , -NHSO ₂ (C _1-6 alkyl), -SO ₂ N(C _1-6 alkyl) ₂ , -SO ₂ NH( C _1-6 alkyl), -SO ₂ NH ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ OC _1-6 alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si( C _1-6 alkyl) ₃ , -OSi(C _1-6 alkyl) ₃ , -C(=S)N(C _1-6 alkyl) ₂ , C(=S)NH(C _1-6 alkyl), C (=S)NH ₂ , -C(=O)S(C _1-6 alkyl), -C(=S)SC _1-6 alkyl, -SC(=S)SC _1-6 alkyl, -P(= O)(OC _1-6 alkyl) ₂ , -P(=O)(C _1-6 alkyl) ₂ , -OP(=O)(C _1-6 alkyl) ₂ , -OP(=O)(OC _{1 -6} alkyl) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, hetero C _1-6 alkyl, hetero C _2-6 alkenyl, hetero C _2-6 alkenyl, hetero C _2-10 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R ^gg substituents joined , =O or =S; where X ^- is a counterion.
The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

The term "hydroxyl" or "hydroxy" refers to the group -OH. The term "substituted hydroxyl" or "substituted hydroxy" by extension refers to a hydroxyl group in which the oxygen atom directly attached to the parent molecule has been replaced with a group other than hydrogen. -OR ^aa , -ON(R ^bb ) ₂ , -OC(=O)SR ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -OC(=O)N(R ^bb ) ₂ , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -OC(=NR ^bb )N(R ^bb ) ₂ , -OS(=O)R ^aa , -OSO ₂ R ^aa , -OSi(R ^aa ) ₃ , -OP(R ^cc ) ₂ , -OP(R ^cc ) ₃ ⁺ X ^- , -OP(OR ^cc ) ₂ , -OP(OR ^cc ) ₃ ⁺ X ^- , -OP( =O)(R ^aa ) ₂ , -OP(=O)(OR ^cc ) ₂ , and -OP(=O)(N(R ^bb )) ₂ where X ⁻ , R ^aa , R ^bb , and R ^cc includes groups selected from (as defined herein).

The term "amino" refers to the group _-NH2 . The term "substituted amino" by extension refers to mono-, di-, or tri-substituted amino. In certain embodiments, a "substituted amino" is a mono- or di-substituted amino group.

The term "monosubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with one hydrogen and one group other than hydrogen, such as -NH(R ^bb ), - NHC(=O)R ^aa , -NHCO ₂ R ^aa , -NHC(=O)N(R ^bb ) ₂ , -NHC(=NR ^bb )N(R ^bb ) ₂ , -NHSO ₂ R ^aa , -NHP( =O)(OR ^cc ) ₂ , and -NHP(=O)(N(R ^bb ) ₂ ) ₂ , where R ^aa , R ^bb and R ^cc are as defined herein, and In the group -NH(R ^bb ), R ^bb is not hydrogen.

The term "disubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with two groups other than hydrogen, such as -N(R ^bb ) ₂ , -NR ^bb C( =O) R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -NR ^bb SO ₂ R ^aa , -NR ^bb P(=O)(OR ^cc ) ₂ , and -NR ^bb P(=O)(N(R ^bb ) ₂ ) ₂ (where R ^aa , R ^bb , and R ^cc are As defined herein, except that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

The term "trisubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with three groups, -N(R ^bb ) ₃ and -N(R ^bb ) ₃ ⁺ X ^- (where R ^bb and X ^- are as defined herein).

The term "sulfonyl" includes -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , and -SO ₂ OR ^aa , where R ^aa and R ^bb are as defined herein. Refers to the selected group.

The term "sulfinyl" refers to the group -S(=O)R ^aa , where R ^aa is as defined herein

The term "acyl" has the general formula -C(=O)R ^X1 , -C(=O)OR ^X1 , -C(=O)-OC(=O)R ^X1 , -C(=O)SR ^X1 , -C(=O)N(R ^X1 ) ₂ , -C(=S)R ^X1 , -C(=S)N(R ^X1 ) ₂ , and -C(=S)S(R ^X1 ), -C(=NR ^X1 )R ^X1 , -C(=NR ^X1 )OR ^X1 , -C(=NR ^X1 ) _SR ^X1 , and -C(=NR ^X1 )N( ^R , where R ^X1 is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted, branched or non-molecular aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or non-molecular heteroaliphatic; cyclic or acyclic, substituted or unsubstituted; Branched or unsubstituted alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, aliphatic oxy, heteroaliphatic oxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphatic thioxy, heteroaliphatic thioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, Mono- or di-aliphatic amino, mono- or di-heteroaliphatic amino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- or di- is heteroarylamino; or the two R ^X1 groups are taken together to form a 5- to 6-membered heterocycle. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO ₂ H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety (for example, aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, Heterocycle, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino , heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, etc., each of which may or may not be further substituted).

The term "carbonyl" refers to ^a group in which the carbon directly attached to the parent molecule is sp ² hybridized, such as an oxygen, nitrogen or sulfur atom, such as a ketone (-C(=O) R ^aa ), carboxylic acid (-CO ₂ H), aldehyde (-CHO), ester (-CO ₂ R ^aa , -C(=O)SR ^aa , -C(=S)SR ^aa ), amide (-C (=O)N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -C(=S)N(R ^bb ) ₂ ), and imine (-C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa ), -C(=NR ^bb )N(R ^bb ) ₂ ), where R ^aa and R ^bb are as defined herein. Substituted with a group.

The term "oxo" refers to the group =O and the term "thiooxo" refers to the group =S.

Nitrogen atoms may be substituted or unsubstituted as valency permits and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O) N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^bb )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O)(OR ^cc ) ₂ , -P(=O)(R ^aa ) ₂ , -P(=O)(N(R ^cc ) ₂ ) ₂ , C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, hetero C _1-10 alkyl, hetero C _2-10 alkenyl, hetero C _2-10 alkynyl, C _3-10 carbocyclyl, 3- to 14-membered heterocyclyl, C _6-14 aryl, and 5- to 14-membered heteroaryl, or two R ^cc groups attached to the N atom are joined to form a 3- to 14-membered heterocyclyl. or form a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently 0, 1, 2 , 3, 4 or 5 R ^dd groups, and where R ^aa , R ^bb , R ^cc , and R ^dd are as defined above.

In certain embodiments, the substituents present on the nitrogen atom are nitrogen protecting groups (also referred to herein as "amino protecting groups"). Nitrogen protecting groups include, but are not limited to, -OH, -OR ^aa , -N(R ^cc ) ₂ , -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , - CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^cc )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N( R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , C _1-10 alkyl (for example, aralkyl, heteroaralkyl), C _2-10 alkenyl, C _2-10 alkynyl, hetero C _1-10 alkyl, hetero C _2-10 alkenyl, hetero C _2-10 alkynyl, Includes C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, Heterocyclyl, aralkyl, aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups and wherein R ^aa , R ^bb , R ^cc , and R ^dd are as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, ^3rd edition, John Wiley & Sons, 1999; Incorporated herein.

For example, nitrogen protecting groups such as amide groups (for example, -C(=O)R ^aa ) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3- Phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacrylamide) ) Acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenyl) azophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl) Includes benzamide.

Nitrogen protecting groups such as carbamate groups (for example, -C(=O)OR ^aa ) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9 -(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10) , 10,10,10-tetrahydrothioxanthyl)] methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilyl Ethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1, 1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenyl yl) ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate mate (Pyoc), 2-(N,N-dicyclohexylcarboxamide)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate ( Alloc), 1-isopropylaryl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio Carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-Methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate , [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate ( Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5 -Benzisoxazolyl methyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate mate, 3,4-dimethoxy-6-nitrobenzylcarbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutylcarbamate , cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamide)benzyl carbamate, 1,1 -dimethyl-3-(N,N-dimethylcarboxamide)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate , isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl- 1-Cyclopropylmethylcarbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethylcarbamate, 1-methyl-1-(p-phenylazophenyl)ethylcarbamate, 1-methyl-1-phenyl Ethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-( trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

Nitrogen protecting groups such as sulfonamide groups (for example, -S(=O) ₂ OR ^aa ) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6- Trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6 -Tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4 -(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.
Other nitrogen protecting groups include, but are not limited to, phenothiazinyl(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole , N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl) ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salt, N-benzylamine , N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N- 9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolilamino N'-oxide, N-1 , 1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethyl aminomethylene)amine, N,N'-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl ) phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(penta acylchromium- or tungsten) amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosamine, amine N-oxide, diphenylphosphineamide (Dpp), dimethylthiophosphineamide (Mpt), diphenyl Thiophosphinamide (Ppt), dialkylphosphoramidate, dibenzylphosphoramidate, diphenylphosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide , pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituents present on the oxygen atom are oxygen protecting groups (also referred to herein as "hydroxyl protecting groups"). Oxygen protecting groups include, but are not limited to, -R ^aa , -N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=O)R ^aa , -CO ₂ R ^aa , -C (=O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -S(=O )R ^aa , -SO ₂ R ^aa , -Si(R ^aa ) ₃ , -P(R ^cc ) ₂ , -P(R ^cc ) ₃ ⁺ X ^- , -P(OR ^cc ) ₂ , -P(OR ^{cc )} ₃ ^{+ _} _{_} ^_ _{_} ^_ _{_ _} where X ⁻ , R ^aa , R ^bb , and R ^cc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, ^3rd edition, John Wiley & Sons, 1999; Incorporated herein.

Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM). ), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2- Methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl , tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydrothiopyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro- 4-Methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7 ,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1- Methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl , p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2, 6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenylmethyl, p,p'-dinitrobenzhydryl, 5-dibenzo Suberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl) ) diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4 "-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS) ), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS) ), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloro Acetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-( Ethylene dithio) pentanoate (levulinoyl dithioacetal), pivaloate, adamantate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ) Ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzylthiocarbonate, 4-ethoxy-1- Naphthyl carbonate, methyldithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthio) methoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3, 3-tetramethylbutyl) phenoxy acetate, 2,4-bis(1,1-dimethylpropyl) phenoxy acetate, chlorodiphenyl acetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate , o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

In certain embodiments, the sulfur atom substituents present on the sulfur atom are sulfur protecting groups (also referred to herein as "thiol protecting groups"). Sulfur protecting groups include, but are not limited to, -R ^aa , -N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=O)R ^aa , -CO ₂ R ^aa , -C (=O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -S(=O )R ^aa , -SO ₂ R ^aa , -Si(R ^aa ) ₃ , -P(R ^cc ) ₂ , -P(R ^cc ) ₃ ⁺ X ^- , -P(OR ^cc ) ₂ , -P(OR ^{cc )} ₃ ^{+ _} _{_} ^_ _{_} ^_ _{_ _} where R ^aa , R ^bb , and R ^cc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, ^3rd edition, John Wiley & Sons, 1999; Incorporated herein.

A "counterion" or "anionic counterion" is a negatively charged group that is associated with a positively charged group to maintain electronic neutrality. Anionic counterions may be monovalent (ie, contain one negative formal charge). Anionic counterions may also be multivalent (ie, contain more than one negative formal charge), such as divalent or trivalent. Exemplary counterions include halide ions (for example, F ⁻ , Cl ⁻ , Br ⁻ , I ⁻ ), NO ₃ ⁻ , ClO ₄ ⁻ , OH ⁻ , H ₂ PO ₄ ⁻ , HCO ₃ ⁻ , HSO ₄ ⁻ , sulfonic acid ion (for example, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1-sulfonic acid-5-sulfonic acid) acids, ethane-1-sulfonic acid-2-sulfonic acid, etc.), carboxylic acid ions (for example, acetic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, gluconic acid, etc.), BF ₄ ⁻ , PF ₄ ^- , PF ₆ ^- , AsF ₆ ^- , SbF ₆ ^- , B[3,5-(CF ₃ ) ₂ C ₆ H ₃ ] ₄ ] ^- , B(C ₆ F ₅ ) ₄ ^- , BPh ₄ ^- , Al(OC(CF ₃ ) ₃ ) ₄ ⁻ , and carborane anions (eg, CB ₁₁ H ₁₂ ⁻ or (HCB ₁₁ Me ₅ Br ₆ ) ⁻ ). Exemplary counterions that may be polyvalent are CO ₃ ^2- , HPO ₄ ^2- , PO ₄ ^3- _, B ₄ O ₇ ^2- , SO ₄ ^2- , S ₂ O ₃ ^2- , carboxylic acid anions. (Examples include tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, malonic acid, gluconic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, salicylic acid, phthalic acid, aspartic acid, glutamic acid, etc.), and carboranes.

As used herein, "leaving group" (LG) is an art-understood term that refers to a molecular fragment that leaves with a pair of electrons in an asymmetric bond cleavage, where the molecular fragment is an anion. It is a neutral or neutral molecule. As used herein, a leaving group can be an atom or group capable of being displaced by a nucleophile. See, eg, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplary leaving groups include, but are not limited to, halogens (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., -OC(=O)SR ^aa , -OC(= O) R ^aa , -OCO ₂ R ^aa , -OC(=O)N(R ^bb ) ₂ , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -OC(=NR ^bb )N(R ^bb ) ₂ , -OS(=O)R ^aa , -OSO ₂ R ^aa , -OP(R ^cc ) ₂ , -OP(R ^cc ) ₃ , -OP(=O) ₂ R ^aa , - OP(=O)(R ^aa ) ₂ , -OP(=O)(OR ^cc ) ₂ , -OP(=O) ₂ N(R ^bb ) ₂ , and -OP(=O)(NR ^bb ) ₂ , (where R ^aa , R ^bb , and R ^cc are as defined herein). as an example as an example

As used herein, the use of the phrase "in at least one case" refers to one, two, three, four, or more, but by way of example, from one to four, from one to three , 1 to 2, 2 to 4, 2 to 3, or 3 to 4 (inclusive).

"Non-hydrogen group" refers to any group defined by the specified variable that is not hydrogen.

"Non-hydrogen atom" refers to any atom other than hydrogen.

These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. This invention is in no way intended to be limited by the above-illustrated list of substituents.

Other Definitions The following definitions are more general terms used throughout this application.

As used herein, the term "salt" refers to any and all salts and encompasses pharmaceutically acceptable salts.

The term "pharmaceutically acceptable salts" means salts that, within the scope of sound medical judgment, are suitable for use in contact with human and lower animal tissue without undue toxicity, irritation, allergic response, etc. salt that is suitable and commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, or acetic, oxalic acids. , maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or using other methods known in the art such as ion exchange. It is a basic salt. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, Camphor sulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate , heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate , methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, Phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. include. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N ⁺ (C _1-4 alkyl) ^4- salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammoniums, quaternary ammoniums and, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl Includes amine cations formed with counterions such as sulfonates and arylsulfonates.

The term "solvate" refers to a compound or its salt form that is associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may, for example, be prepared in crystalline form or may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In certain instances, solvates may be able to be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

The term "hydrate" refers to a compound that is associated with water. Typically, the number of water molecules contained in a hydrate of a compound is a constant ratio to the number of molecules of the compound in the hydrate. Accordingly, a hydrate of a compound may be represented, for example, by the general formula R.xH ₂ O, where R is a compound and x is a number greater than 0. A given compound may form more than one type of hydrate, such as monohydrates (x is 1), lower hydrates (x is greater than 0 and less than 1). , for example, hemihydrate (R·0.5H ₂ O)), and polyhydrate (x is a number greater than 1, for example, dihydrate (R·2H ₂ O) and hexahydrate hydrate (R.6H ₂ O)).

The term "tautomer" or "tautomeric" refers to at least one formal transition of a hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, from a triple bond to a single bond). refers to two or more interconvertible compounds resulting from a bond (or vice versa). The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (ie, reactions that provide pairs of tautomers) may be catalyzed by acids or bases. Exemplary tautomerizations include keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to different enamines.
It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms, or in the arrangement of their atoms in space, are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

Stereoisomers that are not mirror images of each other are termed "diastereomers," and those that are non-superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example when it is attached to four different groups, a pair of enantiomers may exist. An enantiomer can be characterized by the absolute configuration of its asymmetric center, described by the R- and S-sequence rules of Cahn and Prelog, or by its manner of rotation with respect to the plane of polarized light of the molecule, dextrorotatory or Designated as levorotatory (ie, as the (+) or (-) isomer, respectively). Chiral compounds can exist either as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Depending on recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystalline form may predominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

The term "prodrug" refers to a compound that has a cleavable group that, upon solvolysis or under physiological conditions, becomes a compound described herein that is pharmaceutically active in vivo. be. Such examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, although acid-sensitive forms often have advantages in solubility, histocompatibility, or delayed release in mammalian organisms. (see, for example, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reaction of the parent acid with a suitable alcohol, or substituted or unsubstituted These include amides prepared by reaction with amines, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases, it is desirable to prepare double ester type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, aryl, C ₇ -C ₁₂ substituted aryl, and C ₇ -C ₁₂ arylalkyl esters of the compounds described herein. However, sometimes it is preferable.

The terms "composition" and "formulation" are used interchangeably.

The term "gene" refers to a nucleic acid fragment that expresses a particular protein, including regulatory sequences preceding (5' non-coding sequences) or following (3' non-coding sequences) the coding sequence. "Native gene" refers to a gene as it is found in nature with its own regulatory sequences. "Chimeric gene" or "chimeric construct" refers to any gene or construct that is not a native gene and contains regulatory and coding sequences that are not found together in nature. As a result, chimeric genes or constructs have regulatory sequences and coding sequences derived from different sources, or regulatory sequences and coding sequences derived from the same source, but arranged in a manner different from those found in nature. may include those that are "Endogenous gene" refers to a native gene in its natural location in the genome of an organism. A "foreign" gene refers to a gene that is not normally found in the host organism, but is introduced into the host organism by gene transfer. Foreign genes can include native genes inserted into a non-native organism, or chimeric genes. A "transgene" is a gene that is introduced into the genome by a transformation procedure.

The term "histone" refers to highly alkaline proteins found in the nucleus of eukaryotic cells that package and organize DNA into structural units called nucleosomes. These are the major protein components of chromatin, which act as spools around which DNA wraps and play a role in gene regulation. In certain embodiments, the histone is histone H1 (eg, histone H1F, histone H1H1). In certain embodiments, the histone is histone H2A (eg, histone H2AF, histone H2A1, histone H2A2). In certain embodiments, the histone is histone H2B (eg, histone H2BF, histone H2B1, histone H2B2). In certain embodiments, the histone is histone H3 (eg, histone H3A1, histone H3A2, histone H3A3). In certain embodiments, the histone is histone H4 (eg, histone H41, histone H44).

The term "bromodomain" refers to a protein domain that recognizes acetylated lysine residues, such as those on the N-terminal tails of histones. In certain embodiments, the bromodomain of a BET protein comprises a conserved fold that contains approximately 110 amino acids and includes a left-handed bundle of four alpha helices connected by a divergent loop region that interacts with chromatin. share. In certain embodiments, the bromodomain is ASH1L (GenBank ID: gi|8922081), ATAD2 (GenBank ID: gi|24497618), BAZ2B (GenBank ID: gi|7304923), BRD1 (GenBank ID: gi|11321642), BRD2( 1) (GenBank ID: gi|4826806), BRD2(2) (GenBank ID: gi|4826806), BRD3(1) (GenBank ID: gi|11067749), BRD3(2) (GenBank ID: gi|11067749), BRD4(1) (GenBank ID: gi|19718731), BRD4(2) (GenBank ID: gi|19718731), BRD9 (GenBank ID: gi|57770383), BRDT(1) (GenBank ID: gi|46399198), BRPF1 (GenBank ID: gi|51173720), CECR2 (GenBank ID: gi|148612882), CREBBP (GenBank ID: gi|4758056), EP300 (GenBank ID: gi|50345997), FALZ (GenBank ID: gi|38788274), GCN5L2 (GenBank ID: gi|10835101), KIAA1240 (GenBank ID: gi|51460532), LOC93349 (GenBank ID: gi|134133279), PB1(1) (GenBank ID: gi|30794372), PB1(2) (GenBank ID: gi|30794372), PB1(3) (GenBank ID: gi|30794372), PB1(5) (GenBank ID: gi|30794372), PB1(6) (GenBank ID: gi|30794372), PCAF (GenBank ID: gi |40805843), PHIP(2) (GenBank ID: gi|34996489), SMARCA2 (GenBank ID: gi|48255900), SMARCA4 (GenBank ID: gi|21071056), SP140 (GenBank ID: gi|52487219), TAF1(1 ) (GenBank ID: gi|20357585), TAF1(2) (GenBank ID: gi|20357585), TAF1L(1) (GenBank ID: gi|24429572), TAF1L(2) (GenBank ID: gi|24429572), TIF1 (GenBank ID: gi|14971415), avian M28 (GenBank ID: gi|5032179), or WDR9(2) (GenBank ID: gi|16445436).

The term "bromodomain-containing protein" or "bromodomain protein" refers to a protein or variant thereof, wild-type or mutant, natural or synthetic, truncated or complete, containing a protein or variant thereof, such as on the tail of a histone. 2 proteins (e.g. histones) possessing a minimal amino acid sequence sufficient for a functional bromodomain capable of mediating acetyl-lysine molecular recognition of acetylated lysine residues on said protein or histones. Refers to variant. Bromodomain-containing proteins include, for example, fusion proteins comprising a bromodomain and an additional moiety with a desired functionality (eg, a reporter moiety).

A "kinase" is a type of enzyme that transfers a phosphate group from a high-energy donor molecule, such as ATP, to a specific substrate (referred to as phosphorylation). Kinases are part of a larger family of phosphotransferases. One of the largest groups of kinases are protein kinases, which act on specific proteins and modify their activity. Kinases are used extensively in cells to transmit signals and control complex processes. Various other kinases act on small molecules such as lipids, carbohydrates, amino acids, and nucleotides for either signaling or to prime them for metabolic pathways. pathways), act. Kinases are often named after their substrates. More than 500 different protein kinases have been identified in humans. These exemplary human protein kinases include, but are not limited to, AAK1, ABL, ACK, ACTR2, ACTR2B, AKT1, AKT2, AKT3, ALK, ALK1, ALK2, ALK4, ALK7, AMPKa1, AMPKa2, ANKRD3, ANPa, ANPb, ARAF, ARAFps, ARG, AurA, AurAps1, AurAps2, AurB, AurBps1, AurC, AXL, BARK1, BARK2, BIKE, BLK, BMPR1A, BMPR1Aps1, BMPR1Aps2, BMPR1B, BMPR2, BMX, BRAF, BRAFps, BRK, BRSK1, BRSK2, BTK, BUB1, BUBR1, CaMK1a, CaMK1b, CaMK1d, CaMK1g, CaMK2a, CaMK2b, CaMK2d, CaMK2g, CaMK4, CaMKK1, CaMKK2, caMLCK, CASK, CCK4, CCRK, CDC2, CDC7, CDK10, CDK11, CDK2, CDK3, CDK4, CDK4ps, CDK5, CDK5ps, CDK6, CDK7, CDK7ps, CDK8, CDK8ps, CDK9, CDKL1, CDKL2, CDKL3, CDKL4, CDKL5, CGDps, CHED, CHK1, CHK2, CHK2ps1, CHK2ps2, CK1a, CK1a2, CK1aps1, CK1aps2, CK1aps3, CK1d, CK1e, CK1g1, CK1g2, CK1g2ps, CK1g3, CK2a1, CK2a1-rs, CK2a2, CLIK1, CLIK1L, CLK1, CLK2, CLK2ps, CLK3, CLK3ps, CLK4, COT, CRIK, CRK7, CSK, CTK, CYGD, CYGF, DAPK1, DAPK2, DAPK3, DCAMKL1, DCAMKL2, DCAMKL3, DDR1, DDR2, DLK, DMPK1, DMPK2, DRAK1, DRAK2, DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, EGFR, EphA1, EphA10, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8, EphB1, EphB2, EphB3, EphB4, EphB6, Erk1, Erk2, Erk3, Erk3ps1, Erk3ps2, Erk3ps3, Erk3ps4, Erk4, Erk5, Erk7, FAK, FER, FERps, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1, FLT1ps, FLT3, FLT4, FMS, FRK, Fused, FYN, GAK, GCK, GCN2, GCN22, GPRK4, GPRK5, GPRK6, GPRK6ps, GPRK7, GSK3A, GSK3B, Haspin, HCK, HER2/ErbB2, HER3/ErbB3, HER4/ErbB4, HH498, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, HRI, HRIps, HSER, HUNK, ICK, IGF1R, IKKa, IKKb, IKKe, ILK, INSR, IRAK1, IRAK2, IRAK3, IRAK4, IRE1, IRE2, IRR, ITK, JAK1, JAK12, JAK2, JAK22, JAK3, JAK32, JNK1, JNK2, JNK3, KDR, KHS1, KHS2, KIS, KIT, KSGCps, KSR1, KSR2, LATS1, LATS2, LCK, LIMK1, LIMK2, LIMK2ps, LKB1, LMR1, LMR2, LMR3, LOK, LRRK1, LRRK2, LTK, LYN, LZK, MAK, MAP2K1, MAP2K1ps, MAP2K2, MAP2K2ps, MAP2K3, MAP2K4, MAP2K5, MAP2K6, MAP2K7, MAP3K1, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP3K6, MAP3K7, MAP3K8, MAPKAPK2, MAPKAPK3, MAPKAPK5, MAPKAPKps1, MARK1, MARK2, MARK3, MARK4, MARKps01, MARKps02, MARKps03, MARKps04, MARKps05, MARKps07, MARKps08, MARKps09, MARKps10, MARKps11 , MARKps12, MARKps13, MARKps15, MARKps16, MARKps17, MARKps18, MARKps19, MARKps20, MARKps21, MARKps22, MARKps23, MARKps24, MARKps25, MARKps26, MARKps27, MARKps28, MARKps29, MARKps30, MAST1, MAST2, MAST3, MAST4, MASTL, MELK, MER, MET ,MISR2, MLK1, MLK2, MLK3, MLK4, MLKL, MNK1, MNK1ps, MNK2, MOK, MOS, MPSK1, MPSK1ps, MRCKa, MRCKb, MRCKps, MSK1, MSK12, MSK2, MSK22, MSSK1, MST1, MST2, MST3, MST3ps, MST4, MUSK, MYO3A, MYO3B, MYT1, NDR1, NDR2, NEK1, NEK10, NEK11, NEK2, NEK2ps1, NEK2ps2, NEK2ps3, NEK3, NEK4, NEK4ps, NEK5, NEK6, NEK7, NEK8, NEK9, NIK, NIM1, NLK, NRBP1, NRBP2, NuaK1, NuaK2, Obscn, Obscn2, OSR1, p38a, p38b, p38d, p38g, p70S6K, p70S6Kb, p70S6Kps1, p70S6Kps2, PAK1, PAK2, PAK2ps, PAK3, PAK4, PAK5, PAK6, PASK, PBK, PCTAIRE1 ,PCTAIRE2, PCTAIRE3, PDGFRa, PDGFRb, PDK1, PEK, PFTAIRE1, PFTAIRE2, PHKg1, PHKg1ps1, PHKg1ps2, PHKg1ps3, PHKg2, PIK3R4, PIM1, PIM2, PIM3, PINK1, PITSLRE, PKACa, PKACb, PKACg, PKCa, PKCb, PKCd, PKCe, PKCg, PKCh, PKCi, PKCips, PKCt, PKCz, PKD1, PKD2, PKD3, PKG1, PKG2, PKN1, PKN2, PKN3, PKR, PLK1, PLK1ps1, PLK1ps2, PLK2, PLK3, PLK4, PRKX, PRKXps, PRKY, PRP4, PRP4ps, PRPK, PSKH1, PSKH1ps, PSKH2, PYK2, QIK, QSK, RAF1, RAF1ps, RET, RHOK, RIPK1, RIPK2, RIPK3, RNAseL, ROCK1, ROCK2, RON, ROR1, ROR2, ROS, RSK1, RSK12, RSK2, RSK22, RSK3, RSK32, RSK4, RSK42, RSKL1, RSKL2, RYK, RYKps, SAKps, SBK, SCYL1, SCYL2, SCYL2ps, SCYL3, SGK, SgK050ps, SgK069, SgK071, SgK085, SgK110, SgK196, SGK2, SgK2 23, SgK269, SgK288, SGK3, SgK307, SgK384ps, SgK396, SgK424, SgK493, SgK494, SgK495, SgK496, SIK, skMLCK, SLK, Slob, smMLCK, SNRK, SPEG, SPEG2, SRC, SRM, SRPK1, SRPK2, SRPK2ps, SSTK, STK 33, STK33ps, STLK3, STLK5, STLK6, STLK6ps1, STLK6-rs, SuRTK106, SYK, TAK1, TAO1, TAO2, TAO3, TBCK, TBK1, TEC, TESK1, TESK2, TGFbR1, TGFbR2, TIE1, TIE2, TLK1, TLK1ps, TLK2, TLK2ps1, TLK2ps2, TNK1, Trad, Trb1, Trb2, Trb3, Trio, TRKA, TRKB, TRKC, TSSK1, TSSK2, TSSK3, TSSK4, TSSKps1, TSSKps2, TTBK1, TTBK2, TTK, TTN, TXK, TYK2, TYK22, TYRO3, TYRO3ps, ULK1, ULK2, ULK3, ULK4, VACAMKL, VRK1, VRK2, VRK3, VRK3ps, Wee1, Wee1B, Wee1Bps, Wee1ps1, Wee1ps2, Wnk1, Wnk2, Wnk3, Wnk4, YANK1, YANK2, YANK3, YES, YESps, YSK1, Includes ZAK, ZAP70, ZC1/HGK, ZC2/TNIK, ZC3/MINK, and ZC4/NRK.

The terms "composition" and "formulation" are used interchangeably.

The "subject" to which administration is contemplated may be a human (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, minor) or an adult subject (e.g., young adult, middle school). Refers to adults (2011, older adults) or non-human animals. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus or rhesus macaque), a commercially relevant mammal (e.g., a cow, a pig, a horse, a sheep, a goat, a cat, or In some embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be male or female at any stage of development. The non-human animal may be a transgenic or genetically modified animal.

The terms "disease," "disorder," and "condition" are used interchangeably.

The term "biological sample" refers to tissue samples (such as tissue sections and needle biopsies of tissue); cell samples (for example, cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); Samples of whole organisms (such as yeast or bacterial samples); or include cell fractions, fragments or organelles (such as those obtained by lysing a cell and separating its components by centrifugation or otherwise) Refers to any sample. Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsied tissue (e.g., obtained by surgical biopsy or needle biopsy). ), nipple aspirate fluid, breast milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules derived from a first biological sample.

The term "administering," "administering," or "administering" refers to the administration of a compound described herein or a composition thereof into, in, or on a subject. refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing.

The terms "condition," "disease," and "disorder" are used interchangeably.

The terms "treatment," "treating," and "treating" refer to halting, alleviating, delaying the onset of, or inhibiting the progression of the diseases described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (eg, in light of a history of symptoms and/or in light of exposure to a pathogen). Treatment may also be continued even after symptoms have resolved, eg, to delay or prevent recurrence.

An "effective amount" of a compound described herein refers to an amount sufficient to induce a desired biological response, ie, treat a condition. As will be appreciated by those skilled in the art, an effective amount of a compound described herein will depend on the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the subject. May vary depending on factors such as age and health. Effective amounts encompass therapeutic and prophylactic treatments.

A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition, or to delay or minimize one or more symptoms associated with a condition. It is. A therapeutically effective amount of a compound means an amount of the therapeutic agent, alone or in combination with other treatments, that provides a therapeutic benefit in the treatment of the condition. The term "therapeutically effective amount" may encompass amounts that improve overall treatment, reduce or avoid symptoms, signs, or causes of a condition, and/or enhance the therapeutic effectiveness of other therapeutic agents. . In certain embodiments, a therapeutically effective amount is effective to inhibit the activity of a bromodomain-containing protein. In certain embodiments, a therapeutically effective amount is effective to treat a disease described herein. In certain embodiments, a therapeutically effective amount is effective to inhibit the activity of bromodomain-containing proteins and to treat the diseases described herein.

A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent the condition, or one or more symptoms associated with the condition, or to prevent its recurrence. A prophylactically effective amount of a compound means an amount of the therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing the condition. In certain embodiments, a prophylactically effective amount is effective to inhibit the activity of a bromodomain-containing protein. The term "prophylactically effective amount" can cover an amount that improves the overall prophylactic regimen or enhances the prophylactic effectiveness of another prophylactic agent. In certain embodiments, a prophylactically effective amount is effective to prevent a disease described herein. In certain embodiments, a prophylactically effective amount is effective to inhibit the activity of bromodomain-containing proteins and to prevent the diseases described herein.

The term "synergistic" or "synergistic effect" refers to when two or more different agents working together produce an enhanced result when compared to the effect of any one agent working alone. Refers to a phenomenon. For example, a "synergistic" effect is when co-administration of two compounds results in an enhanced biological effect when compared to the biological effect observed when each individual compound is administered in the absence of the other. is achieved when it brings about

The term "inhibition," "inhibiting," "inhibiting," or "inhibitor" refers to the activity of a specific biological process in a cell (e.g., bromodomain and/or bromodomain) as compared to a vehicle. refers to the ability of a compound to reduce, delay, halt, or prevent the activity of a protein it contains. In some embodiments, the term refers to the level of enzyme activity, e.g. It refers to reduction to a statistically significantly lower level. In some embodiments, the term means that the level of enzymatic activity, e.g. Less than %, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4% , less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, 0.001%, or less than 0.0001%.

A compound, pharmaceutical composition, method, use, or kit is considered to "selectively," "specifically," or "competitively" bind to a first protein or chromatin. The compositions, methods, uses, or kits have a binding affinity that is higher than that of the first protein and a second protein or second chromatin that is different from the first chromatin (e.g., about 2 times or more, about 5 times or more, (about 10 times or more, about 30 times or more, about 100 times or more, about 1,000 times or more, or about 10,000 times or more) to the first protein or first chromatin. The compound, pharmaceutical composition, method, use, or kit "selectively," "specifically," or "competitively" modulates (e.g., increases or inhibits) the activity of a bromodomain-containing protein. When a compound, pharmaceutical composition, method, use, or kit exhibits the activity of at least one protein that is different from the bromodomain-containing protein by a greater degree (e.g., about 2 times or more, about 5 times or more) , about 10-fold or more, about 30-fold or more, about 100-fold or more, about 1,000-fold or more, or about 10,000-fold or more).

The term "abnormal activity" refers to activity that deviates from normal activity. The term "increased activity" refers to activity that is higher than normal activity.

"Proliferative disease" refers to a disease caused by abnormal growth or expansion of cells due to doubling (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative diseases include 1) pathological proliferation of normally quiescent cells; 2) pathological migration of cells from their normal location (eg, metastasis of neoplastic cells); 3) matrix It may be associated with pathological expression of proteolytic enzymes such as metalloproteinases (eg, collagenase, gelatinase, and elastase); or 4) pathological angiogenesis, as seen in proliferative retinopathy and tumor metastases. Exemplary proliferative diseases include cancer (ie, "malignant neoplasms"), benign neoplasms, diseases associated with angiogenesis, inflammatory diseases, and autoimmune diseases.

The term "angiogenesis" refers to the physiological process in which new blood vessels are formed from existing vessels. Angiogenesis is distinct from blood vessel development, which is the de novo formation of endothelial cells from mesodermal cell precursors. The first tubes in the developing embryo are formed through vascular development, and then angiogenesis is responsible for most blood vessel growth during normal or abnormal development. Angiogenesis is a vital process in growth and development, as well as in wound healing and granulation tissue formation. However, angiogenesis is also a fundamental step in the transition of tumors from a benign stage to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis can be chemically stimulated by angiogenic proteins such as growth factors (eg, VEGF). "Pathological angiogenesis" refers to abnormal (eg, excessive or insufficient) angiogenesis that results in and/or is associated with disease.

The terms "neoplasm" and "tumor" are used interchangeably and refer to an abnormal mass of tissue, where the growth of the mass exceeds the growth of normal tissue and is consistent with the growth seen in normal tissue. Don't do it. A neoplasm or tumor can be "benign" or "malignant" depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. It may be. A "benign neoplasm" is generally well differentiated, has a characteristically slower growth rate than a malignant neoplasm, and remains localized to its original site. In addition, benign neoplasms do not have the tendency to invade, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenoma, acrochordon, senile hemangioma, seborrheic keratosis, lentigo, and sebaceous hyperplasia. In some cases, certain "benign" tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of neoplastic cells in the tumor, and these tumors are referred to as "premalignant neoplasms." An exemplary pre-malignant neoplasm is a teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplasia) and are characterized by rapid growth with progressive invasion, invasion, and destruction of surrounding tissues. Furthermore, malignant neoplasms generally have the property of metastasizing to distant sites. The term "metastasis," "metastatic," or "metastasize" refers to the spread or movement of cancerous cells from a primary or original tumor to another organ or tissue, typically can be identified by the presence of a "secondary tumor" or "secondary cell mass" of the primary or original tumor histology, rather than of the organ or tissue in which the secondary (metastatic) tumor resides. It is. For example, prostate cancer that has migrated to the bone is said to be metastatic prostate cancer, which includes cancerous prostate cancer cells that grow in bone tissue.

The term "cancer" refers to a malignant neoplasm (Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990). Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; cancer of the adrenal gland; anal cancer; angiosarcoma (for example, lymphangiosarcoma, lymphangiendothelial sarcoma, angiosarcoma) Benign monoclonal gammopathy; Cholangiocarcinoma (for example, cholangiocarcinoma); Bladder cancer; Breast cancer (for example, adenocarcinoma of the breast, papillary carcinoma of the breast, breast cancer ( mammary cancer), medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma) ; bronchial cancer; carcinoid tumor; cervical cancer (e.g. cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g. colon cancer); cancer of the connective tissue; epithelial cancer; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); Esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarcinoma); Ewing's sarcoma; Eye cancer (e.g., intraocular melanoma, retinoblastoma) ; familial hypereosinophilia; gallbladder cancer; gastric cancer (e.g. gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g. head and neck squamous cell carcinoma) , oral cavity cancer (for example, oral squamous cell carcinoma), throat cancer (for example, laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer); hematopoietic cancer (for example, Acute lymphocytic leukemia (ALL) (e.g. B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g. B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g. , B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell CLL); HL) and non-Hodgkin's lymphoma (NHL) (e.g., diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma ( CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodular marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary longitudinal septal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (i.e. Waldenström macroglobulinemia), hairy cell leukemia (HCL), immune large cell lymphoma, precursor B lymphoblastic lymphoma and primary central nervous system B-cell NHL, such as CNS lymphoma; and precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary T-cell NHL, such as angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); one or more of the mixed leukemia/lymphomas as described above; and lymphomas such as multiple myeloma (MM); heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease); vascular disease. blastoma; hypopharyngeal cancer; inflammatory myofibroblastic tumor; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma, also known as Wilms tumor, renal cell carcinoma); liver cancer (e.g., liver cancer); cell carcinoma (HCC), malignant hepatocellular carcinoma); lung cancer (e.g. bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung) leiomyosarcoma (LMS); mast cell cancers of the muscles; myelodysplastic syndromes (MDS); mesothelioma; myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential Thrombocytosis (ET), idiopathic myeloid metaplasia (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis); neuroendocrine cancer (e.g., gastrointestinal pancreatitis); tubular neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma ; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous tumor (IPMN), islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; Germinal tumors (PNTs); plasma cell neoplasms; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (for example, prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; cancer of the salivary glands; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthocytoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendiceal cancer); soft tissue sarcoma (e.g., Malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovial tumor; testicular cancer ( Thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancer. Includes cancer (eg, Paget's disease of the vulva).

The term "inflammatory disease" refers to a disease caused by, resulting from, or resulting in inflammation. The term "inflammatory disease" can also refer to a dysregulated inflammatory response that causes an exaggerated response by macrophages, granulocytes, and/or T lymphocytes, leading to abnormal tissue damage and/or cell death. Inflammatory diseases can be either acute or chronic inflammatory conditions and can result from infectious or non-infectious causes. Inflammatory diseases include, but are not limited to, atherosclerosis, arteriosclerosis, autoimmune diseases, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, and osteoarthritis. , tendonitis, bursitis, psoriasis, cystic fibrosis, osteoarthritis, rheumatoid arthritis, inflammatory arthritis, Sjögren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing Spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g. type I), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Goodpasture's disease, mixed connective tissue disease, sclerosing bile ducts inflammation, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory skin disease, common interstitial pneumonia (UIP), asbestosis, silicosis, bronchiectasis, beryllium toxicity, talc, pneumoconiosis , sarcoidosis, desquamative interstitial pneumonia, lymphointerstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related forms of vasculitis (temporal arteritis and polyarteritis nodosa), inflammatory skin diseases, delayed hypersensitivity reactions (e.g. poison ivy dermatitis), pneumonia, airway inflammation, adult respiratory distress syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, Hay fever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host versus graft Rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enteritis , epicondylitis, epididymitis, fasciitis, connective tissue inflammation, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, testis inflammation, osteitis, otitis media, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonia, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, Orchitis, tonsillitis, urethritis, cystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, vasculitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse spinal cord inflammation, necrotizing fasciitis, and necrotizing enterocolitis. Inflammatory diseases of the eye include, but are not limited to, post-surgical inflammation.

"Autoimmune disease" refers to a disease that results from an inappropriate immune response of a subject's body to substances and tissues normally present within the body. In other words, the immune system mistakes a part of the body for a pathogen and attacks its own cells. This may be restricted to one organ (as in autoimmune thyroiditis) or specific in different locations (as in Goodpasture's disease, which can affect the basement membrane in both the lungs and kidneys). Organizations may also be involved. Treatment of autoimmune diseases typically involves immunosuppression, eg, drugs that reduce the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture syndrome, necrotizing vasculitis, lymphadenitis, periarteritis nodosa, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis/polymyositis, antiphospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjögren's syndrome, Crohn's disease, Reiter's syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, and cardiomyopathy.

The term "neurological disease" refers to any disease of the nervous system, including the central nervous system (brain, brainstem and cerebellum), peripheral nervous system (including cranial nerves), and autonomic nervous system (parts of which include the central and peripheral nervous system). (located in both systems). Neurodegenerative diseases refer to types of neurological diseases characterized by the loss of nerve cells, including but not limited to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and tauopathies (frontotemporal dementia). including), and Huntington's disease. Examples of neurological diseases include, but are not limited to, headaches, stupor and coma, dementia, seizures, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmology, movement disorders, demyelinating diseases. , spinal cord disorders, and disorders of peripheral nerves, muscles, and neuromuscular junctions. Addiction and mental illness include, but are not limited to, bipolar disorder and schizophrenia, which are also encompassed within the definition of neurological illness. Further examples of neurological diseases are acquired epileptic aphasia; acute disseminated meningitis; adrenoleukodystrophy; corpus callosum deficiency; agnosia; Aicardi syndrome; Alexander disease; Alpers disease; alternating hemiplegia; Alzheimer's disease; Amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cyst; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformation; Asperger syndrome; telangiectasia Sexual ataxia; attention deficit hyperactivity disorder; autism; autonomic neuropathy; back pain; Batten disease; Behcet's disease; Bell's palsy; benign essential blepharospasm; benign focal muscular atrophy; benign Increased intracranial pressure; Binswanger disease; blepharospasm; Bloch-Sulzberger syndrome; brachial nerve sac injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal cord tumors; Brown-Séquard syndrome; Canavan disease; hand Root canal syndrome (CTS); burning pain; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; cholera; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome ; Coffin-Lowry syndrome; coma including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cephalic arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative Traumatic disorders; Cushing's syndrome; giant cell inclusion body disease (CIDB); cytomegalovirus infection; dancing eyes and feet syndrome; Dandy-Walker syndrome; Dawson's disease; Demorcia syndrome; Degerin-Krumpke paralysis; dementia; skin Myositis; diabetic neuropathy; diffuse sclerosis; autonomic neuropathy; dysgraphia; dyslexia; dystonia; early infantile epileptic encephalopathy; turcic cavity syndrome; encephalitis; encephalocele; cerebral trigeminal angiomatosis; epilepsy ; Erb's palsy; essential tremor; Fabry disease; Fahr disease; syncope; familial spastic paraplegia; febrile seizures; Fisher syndrome; Friedreich's ataxia; frontotemporal dementia and other "tauopathies"; Gaucher disease ; Gerstmann syndrome; giant cell arteritis; giant cell inclusion body disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1-associated myelopathy; Hallerholden-Spatz syndrome; head trauma; headache; hemifacial spasm; genetics spastic paraplegia; hereditary ataxia of the polyneuritis type; herpes zoster; herpes zoster; Hirayama disease; HIV-associated dementia and neurological disorders; (see also neurological symptoms of AIDS); holoprosencephaly; Huntington's disease Other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; adrenocortical hypermormonism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; pigmentary ataxia; Infantile phytanic acid storage disease; infantile Refsum disease; epilepsy; inflammatory myopathy; intracranial cyst; increased intracranial pressure; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsborne syndrome; Klippel-Feil syndrome ; Krabbe disease; Kugelberg-Welander disease; Kuru disease; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh syndrome; Lennox-Gastaut syndrome; Lesch-Nyhan syndrome ; leukodystrophy; Lewy body dementia; gyri defects; locked-in syndrome; Lou Gehrig's disease (also known as motor neuron disease or amyotrophic lateral sclerosis); lumbar discopathy; Lyme disease - neurological sequelae; Macrencephaly; Megalencephaly; Melkerson-Rosenthal syndrome; Meniere's disease; Meningitis; Menkes' disease; Metachromatic leukodystrophy; Microcephaly; Migraine; Miller-Fisher syndrome; mini-strokes; mitochondrial myopathy; Moebius syndrome; monomeric amyotrophy; motor neuron disease; moyamoya disease; mucopolysaccharidosis; multi-infarct dementia; focal motor neuropathies; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; myelinolytic diffuse sclerosis ( myelinoclastic diffuse sclerosis); myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; malignant syndrome; neurological symptoms of AIDS; neurological symptoms of lupus Neurological sequelae of lupus; neurogenic myotonia; neuronal ceroid lipofuscinosis; nerve cell migration disorder; Niemann-Pick disease; O'Sullivan-McLeod syndrome; occipital neuralgia; subclinical spinal fusion Occult spinal dysraphism sequence; Otahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson's disease; congenital Paramyotonia; paraneoplastic diseases; paroxysmal attacks; Parry-Romberg syndrome; Perizeus-Merzbacher disease; periodic quadriplegia; peripheral neuropathy; painful neuropathy and neuropathic pain ; persistent vegetative state; pervasive developmental disorder; photo-sneeze reflex; phytanic acid storage disease; Pick's disease; pinched nerve; pituitary tumor; polymyositis; porencephaly; post-polio syndrome; post-herpetic neuralgia ( Post-measles encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion disease; progressive hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (types I and II); Rasmussen encephalopathy; reflex sympathetic dystrophy; Refsum disease; Repetitive motion disorders; Repetitive stress injuries; Restless legs syndrome; Retrovirus-associated myelopathy; Rett syndrome; Reye syndrome; Saint Vitus Dance; Sandhoff disease ; Schilder's disease; schizencephaly; septal optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjögren's syndrome; sleep apnea; Sotos syndrome; spasticity ); Spina bifida; Spinal cord injury; Spinal cord tumor; Spinal muscular atrophy; General stiffness syndrome; Stroke; Sturge-Weber syndrome; Subacute sclerosis panencephalitis; Subarachnoid hemorrhage; Subcortical arteriosclerosis encephalopathy; Sydenham chorea; Syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; spinal cord tethering syndrome; Thomsen's disease; thoracic outlet syndrome; trigeminal neuralgia; Todd's palsy; Tourette's syndrome; transient ischemic attack; transmission Transverse myelitis; Brain trauma; Tremor; Trigeminal neuralgia; Tropical spastic paraplegia; Tuberous sclerosis; Vascular dementia (multi-infarct dementia); Temporal arteritis von Hippel-Lindau disease (VHL); Wallenberg syndrome; Werdnig-Hoffmann disease; West syndrome; whiplash syndrome; Williams syndrome; Wilson disease; and Zellweger syndrome.

The term "metabolic disorder" refers to any disorder involving alterations in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or combinations thereof. Metabolic disorders are associated with either deficiencies or excesses in metabolic pathways resulting in imbalances in the metabolism of nucleic acids, proteins, lipids, and/or carbohydrates. Factors that affect metabolism include, but are not limited to, endocrine (hormone) control systems (e.g., enteroendocrine hormones, including the insulin pathway, GLP-1, PYY, etc.), neural control systems (e.g., brain GLP-1), etc. Examples of metabolic disorders include, but are not limited to, diabetes (eg, type I diabetes, type II diabetes, gestational diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, and obesity.

BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings constitute a part of this specification and, together with the description, serve to illustrate several aspects of the invention and to explain the principles of the invention. .

Figures 1a-1d. Rational design of bivalent BET family bromodomain inhibitors. Figure 1a shows the structure and activity of the prototype BET family bromodomain inhibitor JQ1. Figure 1b shows the crystal structure of BRD4 (1) together with JQ1 (pdb 3MXF). JQ1 binds to BRD4(1) through its acetyl-lysine-mimicking triazole moiety and has solvent exposed regions at the thiophene 2-position and the diazepine 6-position, which are Suitable for chemical modification (indicated by an arrow). Figure 1c shows the primary structure of human BRD4. The domain structure describes a potential dimeric JQ1 analog in which the two bromodomains are intra- and/or intermolecularly bridged, joined through the C6 and C2 positions. Figure 1d shows the general chemical structure and design of the dimeric JQ1 molecule. Linkage sites at the 6-position of the diazepine and the 2-position of the thiophene are indicated.

Figures 2a-2b. Homodimeric bivalent inhibitor. Figure 2a shows that the (6+6) homodimer did not increase biological or cellular activity. Figure 2b shows that the (2+2) homodimer showed a 20-fold improved inhibitory activity against BRD4(1), but this was not translated into cellular activity. AlphaScreen™ and cell data points represent at least 2 or 4 replicates ±SD, respectively.

Figures 3a-3e. Heterodimeric bivalent inhibitors and activity optimization. Figures 3a and 3b show general chemical structures of heterodimeric bivalent inhibitors that vary in both (a) linker length and (b) stereochemistry. Figure 3c shows that the prototype BRD4 inhibitor JQ1 or A heat map of dimeric compound activity (IC ₅₀ ) compared to I-BET151 (in bold) is shown. All biochemical and cellular data represent at least two or four replicates, respectively. Figure 3d shows IC ₅₀ curves illustrating the differences in intensity between different (6+2)-PEG1 diastereomers. Figure 3e shows that the efficacy of the heterodimeric compound was confirmed by Bromoscan and showed increased activity against bromodomains 1, 2, tandem bromodomain constructs, and full-length BRD4. Biochemical and cellular data points represent at least 2 or 4 replicates ± SD, respectively.

Figures 4a-4d. Biochemical and physicochemical properties of bivalent inhibitors. Figure 4a shows that the heterodimeric compound (6S+2S)-PEG1 completely shifted BRD4(1) to the dimeric state when added in a 1:2 ratio, but in excess of (6R+2R)-PEG1. PEG1 or JQ1 indicates that size exclusion chromatography failed to shift the monomer peak. Figure 4b shows that (6S+2S)-PEG1 bound to BRD4(1) in a 1:2 ratio, indicating dimerization, whereas JQ1 bound in a 1:1 ratio. Isothermal titration calorimetry data shown. Figure 4c shows immunoblots for BRD4, MYC, and actin after 2 h treatment of MV4;11 cells with (6S+2S)-PEG1 or JQ1 at the indicated concentrations. Figure 4d shows immunoblots for BRD4, MYC, HEXIM1, and actin after treatment of MV4;11 cells with (6S+2S)-PEG1 or JQ1 at 10 nM for the indicated time points.

Figures 5a-5g. Kinetic and anti-tumor advantage of dual BET bromodomain inhibition. Figure 5a shows the chemical structure of MT1. Figure 5b shows MT1, BRD4(1) biochemical and MV;411 and NMC797 cellular activities. Biochemical and cellular data represent at least two or four replicates ± SD, respectively. Figure 5c shows that MT1 induced dimerization of recombinant BRD4 (1) by AlphaScreen™; mean ± SD of triplicates; normalized to dimethyl sulfoxide vehicle. Figure 5d shows the co-crystal structure of MT1 bound to two BRD4(2) monomers. Figure 5e shows the co-crystal structure, which explains the hydrophobic pocket where MT1 binds between the two bromodomain monomers. Figure 5f shows immunoblots for BRD4, PARP-cleaved, cleaved caspase 3, MYC, HEXIM1 and actin from MV4;11 cells treated with 100 nm MT1 for the indicated times. Figure 5g shows early and late apoptotic and healthy MV4;11 cells ( percentage). Error bars represent the SD of three biological replicates. Figure 5h. Figure 5i.

Figures 6a-6b. Activity of (S)- and (R)-JQ1 and I-BET151. Figure 6a shows the chemical representation of the S and R enantiomers of JQ1 and I-BET151. Figure 6b shows the biochemical and cellular activities of the S and R enantiomers of JQ1 and I-BET151. Biochemical and cellular data points represent at least 2 or 4 replicates ±SD, respectively.

Figures 7a-7b. SAR of (6+2)-PEG analogs. Figure 7a shows chemical representations of (6+2)-PEG analogs with different linker lengths (n). Figure 7b shows the molecular weight (MW), logarithm of partition coefficient (cLogP), total polar surface area (tPSA), and biochemical and cellular potencies of (6+2)-PEG analogs. Shows SAR characteristics.

Figures 8a-8f. SAR of hetero- and homodimers of I-BET151 and JQ1. Figures 8a, 8c and 8e show chemical representations of hetero- and homodimers of I-BET151 and JQ1 with different linker lengths (n). Figures 8b, 8d, and 8f depict the hetero- and The SAR properties of the homodimer are shown. Figures 8a, 8c and 8e show chemical representations of hetero- and homodimers of I-BET151 and JQ1 with different linker lengths (n). Figures 8b, 8d, and 8f depict the hetero- and The SAR properties of the homodimer are shown. Figures 8a, 8c and 8e show chemical representations of hetero- and homodimers of I-BET151 and JQ1 with different linker lengths (n). Figures 8b, 8d, and 8f depict the hetero- and The SAR properties of the homodimer are shown.

Figures 9a-9b. Cassette PK properties of bivalent inhibitors. Figures 9a and 9b show PK parameters of mice 5-in-1 cassette PK. Five compounds (1 mg/kg) were administered intravenously to CD1 mice (n=3). Figures 9a and 9b show mouse PK parameters for five in one cassette PK. Five compounds (1 mg/kg) were administered intravenously to CD1 mice (n=3).

Figures 10a-10b. Individual PK properties of bivalent inhibitors. Figure 10a shows PK parameters of mice single PK. (6S+2S)-PEG0 (50 mg/kg) was administered intravenously to CD1 mice (n=3). Figure 10b shows mouse PK parameters for a single PK. (6S+6S)-PEG7 (50 mg/kg) was administered intravenously to CD1 mice (n=3).

Figure 11 shows the apoptotic advantage of MT1 over JQ1 by flow cytometry. Initial and Late apoptotic and healthy MV4; 11 cells (percent). The gating used here and in Figure 5g is shown. Percentages are shown as the mean±SD of three biological replicates.

Figure 12 shows the increased potency of heterodimeric compounds for BET family bromodomains.

Figures 13a-13e. In vivo efficacy of dual BET bromodomain inhibition. FIG. 13a shows 44.2 μmol/kg (n=8) from day 7 to day 21 after initial injection of MV4;11 leukemic cells in a disseminated xenograft model. Radiance in the lumen of mice treated with either MT1 at 22.1 μmol/kg (n=9), JQ1 at 44.2 μmol/kg (n=8), or vehicle (n=8) (luminal radiance) (mean±SEM). Figure 13b shows the percentage of mCherry ⁺ leukemic cells (mean ± SEM) in flushed bone marrow from mice in Figure 13a. Figure 13c shows images of radiance in the lumen of three representative cages before (day 11) and after (day 45) treatment. MT1 (n=11), JQ1 (n=11), or vehicle (n=11) at days 17-28 and after the initial injection of MV4;11 leukemic cells in a disseminated xenograft model. It was administered once daily on days 31-35 at 44.2 μmol/kg. Figure 13d shows the radiance (mean ± SEM) in the lumen of mice from Figure 13c treated with MT1, JQ1 or vehicle. Figure 13e shows a simplified plot of Kaplan-Meier survival for mice from Figure 13c treated with MT1, JQ1 or vehicle. ns=not significant, ^* P=0.01-0.05, ^** P=0.001-0.01, ^*** P=0.0001-0.001, ^*** P<0. 0001. (Kaplan-Meier: Mantel-Cox test; all other comparisons: unpaired two-tailed Welch's t test, no correction for multiple comparisons).

Figure 14 shows biological data for the heterodimeric bivalent inhibitor (6S+2S)-PEG1-ether.

Figure 15 shows that MT1 exhibits limited activity against a panel of human recombinant ligands and ion receptors. MT1 (1 μM) was screened against a panel of 55 ligand receptors, ion channels, and transport proteins using an established and widely used commercial assay (ExpresSProfile; CEREP, Paris, France). Ta. Competitive binding of MT1 to agonists (gray bars) and antagonists (black bars) of the indicated receptors, ion channels and transport proteins is depicted. Competitive binding of diazepam to central benzodiazepine receptors is designated by the symbol "benzodiazepine (central)." Error bars represent the range of two independent measurements from the mean. Complete data is provided in FIG. 20.

Figure 16 shows BRD4(1) dimerized Alpha. Differently tagged (His and GST) BRD4(1) constructs are incubated in the presence of drugs, then glutathione donor and nickel acceptor AlphaScreen™ beads are added to the solution and luminescence is monitored. Compound-mediated dimerization was thus determined. Data points were performed in triplicate and represent the mean±SD.

Figures 17a-17c. Co-crystal structure of MT1 with BRD4(2). Figure 17a shows an unbiased electron density map around MT1. Figures 17b and 17c show the single binding mode of JQ1/BRD4(1) (PDB: 3MXF, gray) and the two binding modes of MT1 in each binding pocket of two BRD4(2) (yellow). , indicating the superposition of crystallized units.

FIG. 18 shows CETSA of JQ1 and MT1. Cells were treated with JQ1, MT1, or DMSO and then subjected to heat shock to denature and aggregate proteins. Cells were lysed and cleared by centrifugation, and the stabilized proteins in the supernatant were analyzed by SDS-PAGE and immunoblotting, performed in triplicate.

Figure 19 shows the tolerability and toxicity of MT1. In a disseminated leukemia (MV4; 11) xenograft model, mice received vehicle (n=11), JQ1 (n=11), or MT1 (n=1) at 44 μmol/kg for the indicated days. 11). Mice were weighed at the indicated time points. Data points represent the mean±SD.

Figure 20 shows a gel of purified protein. 2 μg of each recombinant protein used in this study was run on an SDS-PAGE gel and then stained with Coomassie Blue dye. Arrows indicate the desired major protein bands.

Figure 21 provides an overview of MT1 binding studies (ExpresSProfile; CEREP, Paris, France) performed on a panel of human recombinant ligands and ion receptors. Figure 21 provides an overview of MT1 binding studies (ExpresSProfile; CEREP, Paris, France) performed on a panel of human recombinant ligands and ion receptors. Figure 21 provides an overview of MT1 binding studies (ExpresSProfile; CEREP, Paris, France) performed on a panel of human recombinant ligands and ion receptors. Figure 21 provides an overview of MT1 binding studies (ExpresSProfile; CEREP, Paris, France) performed on a panel of human recombinant ligands and ion receptors. Figure 21 provides an overview of MT1 binding studies (ExpresSProfile; CEREP, Paris, France) performed on a panel of human recombinant ligands and ion receptors.

Figure 22 shows data collection and refinement statistics (molecular replacement).

Figure 23 shows an exemplary synthetic scheme for the preparation of MT1.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS The present disclosure describes methods of binding to bromodomains and/or bromodomain-containing proteins represented by formulas (I), (II), (III), (IV), (V), and (VI). Provides a compound that can be used. In certain embodiments, the compounds described herein are homodimers of JQ-1 or analogs of JQ-1 (e.g., compounds of formulas (I), (II), and (III) ). In certain embodiments, the compound is a homodimer of I-BET151 or an analog thereof (eg, a compound represented by formula (VI)). In other embodiments, the compounds described herein are heterodimers (formulas (IV) and (V)). In certain embodiments, the compounds described herein bind to a bromodomain (eg, a bromodomain of a bromodomain-containing protein). In certain embodiments, the compounds described herein may bind into the pocket of the bromodomain, and facilitate interactions between the bromodomain and acetylated lysine residues of a second protein (e.g., a histone). It may be disrupted. In certain embodiments, the compounds described herein bind to two different sites on a single protein simultaneously. For example, compounds described herein may bind simultaneously to BD1 and BD2 of BRD4. In certain embodiments, compounds provided herein may bind simultaneously to BD1 and BD2 of BRD2. In certain embodiments, compounds provided herein may bind simultaneously to BD1 and BD2 of BRD3. In certain embodiments, compounds provided herein may bind simultaneously to BD1 and BD2 of BRDT.

Compounds described herein may also modulate (eg, inhibit) the activity of bromodomains and/or bromodomain-containing proteins. Also provided in this disclosure are pharmaceutical compositions, methods, uses, and kits useful for modulating (eg, inhibiting) the activity of bromodomain-containing proteins (eg, transcription factors). There is also.

The compounds, pharmaceutical compositions, methods, uses, and kits are useful for treating diseases associated with bromodomains, diseases associated with bromodomain-containing proteins, diseases associated with activity (e.g., abnormal activity) of bromodomains, and diseases associated with bromodomains. It may be useful to treat and/or prevent diseases associated with activity (eg, abnormal activity) of the contained protein. Exemplary diseases that may be prevented and/or treated with compounds described herein include proliferative diseases (e.g., cancer, benign neoplasms, pathological angiogenesis, inflammatory diseases, and autoimmune diseases). , including autoimmune diseases, cardiovascular diseases, viral infections, fibrotic diseases, neurological diseases, metabolic diseases, endocrine diseases, and radiotoxicity.

The compounds, pharmaceutical compositions, methods, uses, and kits are also useful for male contraception and for preventing and/or treating viral infections (e.g., by inhibiting viral replication, by killing viruses). It may also be useful for doing so.

Compounds In one aspect, the invention provides novel compounds useful as bromodomain inhibitors. In certain embodiments, the compounds provided herein are homodimers of JQ-1 or analogs thereof (e.g., compounds of formulas (I), (II), and (III)) It is. In certain embodiments, the compound is a homodimer of I-BET151 or an analog thereof (eg, a compound of formula (VI)). In other embodiments, the compounds described herein are heterodimers comprising JQ-1 or JQ-1-like monomers and I-BET151 or I-BET151-like monomers (for example, formula ( IV) and (V)). For any of the compounds provided herein, the linker joining the two monomers can be any linking group containing from 1 to 40 carbon atoms. Linkers can be substituted or unsubstituted, branched or unbranched. In certain embodiments, the linker is an alkylene linker. In certain embodiments, the linker is a heteroalkylene linker (eg, a polyether linker such as a polyethylene glycol linker). In certain embodiments, the linker is an optionally substituted alkylene, an optionally substituted heteroalkylene, an optionally substituted alkenylene, an optionally substituted heteroalkenylene, an optionally substituted alkynylene, an optionally substituted heteroalkynylene, an optionally substituted carbocyclylene, an optionally substituted heterocyclylene, an optionally substituted arylene. , and optionally substituted heteroarylene, or any combination thereof.

Compound represented by formula (I) As generally described herein, a compound represented by formula (I) is a homogeneous compound composed of two monomers that are JQ-1 or an analog thereof. It is a dimer. The monomers of the compound of formula (I) are linked together through the 2 and 6 positions of the monomer (referred to herein as a (2+6) homodimer).
In one aspect, the invention provides formula (I):
and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof And in the formula:
L is a linker containing 1 to 40 carbon atoms, including optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene , optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene, or any combination thereof;
In any case, R ¹ , R ² , R ³ , and R ⁴ are independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted is carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ;
In each case, R ^a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or oxygen protecting group. is;
In each instance, R ^b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or nitrogen protecting group. or optionally two R ^3b are joined together with intervening atoms to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
In each case, R ^c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or sulfur protecting group. is;
R ⁵ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclylalkyl, is optionally substituted carbocyclylalkyl, optionally substituted acyl, -OR ^5a , or -N(R ^5b ) ₂ ;
In any case, R ^5a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaryl. is an alkyl, an optionally substituted heterocyclylalkyl, an optionally substituted carbocyclylalkyl, an optionally substituted acyl, or an oxygen protecting group;
In any case, R ^5b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaryl. alkyl, optionally substituted heterocyclylalkyl, optionally substituted carbocyclylalkyl, optionally substituted acyl, or nitrogen protecting group; or optionally two R ^5b are joined together with intervening atoms to form optionally substituted heterocyclyl or optionally substituted hetero forming an aryl; and m in each case is independently 0, 1, 2, 3, 4, or 5.

In certain embodiments, the compound represented by formula (I) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. It is.

In certain embodiments, the compound represented by formula (I) has formula (Ia):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; During the ceremony:
L ¹ is a linker containing 1 to 36 carbon atoms, including optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclyl or any combination thereof.

In certain embodiments, the compound represented by formula (Ia) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (I) has formula (Ib):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; During the ceremony:
L ² is a linker containing 1 to 34 carbon atoms, including optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclyl and each R N is independently hydrogen, optionally substituted alkyl, or any combination thereof; and each R ^N is independently hydrogen, optionally substituted alkyl , optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or nitrogen protecting group.

In certain embodiments, the compound represented by formula (Ib) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (I-b) has formula (I-c):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; During the ceremony:
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In certain embodiments, the compound represented by formula (I-c) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (I-c) has formula (I-d):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (Ic) has formula (Ie):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (I-b) has formula (If):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (If) is represented by formula (Ig):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (I) has formula (Ih):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (Ih) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (I-a) has formula (I-i):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (I-i) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (I-b) is represented by formula (I-j):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (Ij) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (I-c) is represented by formula (I-k):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (Ik) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (I) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. It is.

Examples of compounds represented by formula (I) include, but are not limited to, the following:
and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof.

Compound Represented by Formula (II) As generally described herein, a compound represented by Formula (II) is a homodimer composed of two monomers; mer is JQ-1 or an analog thereof. The monomers of the compound of formula (II) are linked together through the 6-position of the monomer (referred to herein as a (6+6) homodimer). Provided herein includes formula (II):
and their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs. , in the formula:
L is a linker containing 1 to 40 carbon atoms, including optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene , optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene, or any combination thereof;
In any case, R ¹ , R ² , R ³ , and R ⁴ are independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted is carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ;
In each case, R ^a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or oxygen protecting group. is;
In each instance, R ^b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or nitrogen protecting group. or optionally two R ^3b are joined together with intervening atoms to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
In each case, R ^c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or sulfur protecting group. is;
R ⁵ is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or oxygen protecting group; and in each case m is independently 0 , 1, 2, 3, 4, or 5.

In certain embodiments, the compound represented by formula (II) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. It is.

In certain embodiments, the compound represented by formula (II) has formula (II-a):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; During the ceremony:
L ¹ is a linker containing 1 to 36 carbon atoms, including optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclyl or any combination thereof.

In certain embodiments, the compound represented by formula (II-a) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (II) has formula (II-b):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; During the ceremony:
L ² is a linker containing 1 to 34 carbon atoms, including optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclyl and each R N is independently hydrogen, optionally substituted alkyl, or any combination thereof; and each R ^N is independently hydrogen, optionally substituted alkyl , optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or nitrogen protecting group.

In certain embodiments, the compound represented by formula (II-b) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (II-b) is represented by formula (II-c):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; During the ceremony:
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In certain embodiments, the compound represented by formula (II-c) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (II-b) is represented by formula (II-d):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (II) has formula (II-e):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (II-e) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (II-a) is represented by formula (II-f):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (II-f) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (II-b) is represented by formula (II-g):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (II-g) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (II-c) is represented by formula (II-h):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (II-h) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (II) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. It is.

Examples of compounds represented by formula (II) include, but are not limited to, the following:
and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof.

Compound represented by formula (III) As generally described herein, the compound represented by formula (III) is a homodimer composed of two monomers; mer is JQ-1 or an analog thereof. The monomers of the compound of formula (III) are linked together through the 2-position of the monomer (referred to herein as a (2+2) homodimer). Provided herein includes formula (III):
and their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs. , in the formula:
L is a linker containing 1 to 40 carbon atoms, including optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene , optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene, or any combination thereof;
R ^{1 ,} R ² , R ³ , and R ⁴ in each instance are independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted alkyl , optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ;
In each case, R ^a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or oxygen protecting group. is;
In each instance, R ^b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or nitrogen protecting group. or optionally two R ^3b are joined together with intervening atoms to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
In each case, R ^c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or sulfur protecting group. is;
R ⁵ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclylalkyl, is optionally substituted carbocyclylalkyl, optionally substituted acyl, -OR ^5a , or -N(R ^5b ) ₂ ;
In any case, R ^5a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaryl. is an alkyl, an optionally substituted heterocyclylalkyl, an optionally substituted carbocyclylalkyl, an optionally substituted acyl, or an oxygen protecting group;
In any case, R ^5b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaryl. alkyl, optionally substituted heterocyclylalkyl, optionally substituted carbocyclylalkyl, optionally substituted acyl, or nitrogen protecting group; or optionally two R ^3b are joined together with intervening atoms to form optionally substituted heterocyclyl or optionally substituted hetero forming an aryl; and m in each case is independently 0, 1, 2, 3, 4, or 5.

In certain embodiments, the compound represented by formula (III) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. It is.

In certain embodiments, the compound represented by formula (III) has formula (III-a):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; During the ceremony:
L ² is a linker containing 1 to 34 carbon atoms, including optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclyl and each R N is independently hydrogen, optionally substituted alkyl, or any combination thereof; and each R ^N is independently hydrogen, optionally substituted alkyl , optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or nitrogen protecting group.

In certain embodiments, the compound represented by formula (III-a) has the following formula:
It is expressed as

In certain embodiments, the compound represented by formula (III-a) is represented by formula (III-a-1):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; During the ceremony:
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In certain embodiments, the compound represented by formula (III-a-1) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (III-a) is represented by formula (III-b):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; During the ceremony:
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In certain embodiments, the compound represented by formula (III-b) is represented by formula (III-c):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (III) has formula (III-d):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (III-d) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (III-a) is represented by formula (III-e):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (III-e) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (III-b) is represented by formula (III-f):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (III-f) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (III) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. It is.

In certain embodiments, the compound represented by formula (III) is:
and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof.

Compound of Formula (IV) As generally described herein, a compound of Formula (IV) is a heterodimer composed of two monomers, where one The monomer of is JQ-1 or an analog thereof, and the other monomer is I-BET151 or an analog thereof. The monomers of the compound represented by formula (IV) are linked through the 6-position of the JQ-1 or JQ-1-like monomer. Provided herein is formula (IV):
and their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs. , in the formula:
L is a linker containing 1 to 40 carbon atoms, including optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene , optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene, or any combination thereof;
In any case, R ¹ , R ² , R ³ , and R ⁴ are independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted is carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ;
In each case, R ^a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or oxygen protecting group. is;
In each instance, R ^b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or nitrogen protecting group. or optionally two R ^3b are joined together with intervening atoms to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
In each case, R ^c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or sulfur protecting group. is;
m in each case is independently 0, 1, 2, 3, 4, or 5;
In any case, R ⁶ , R ⁷ , R ¹⁰ , and R ¹¹ are independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted is carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ;
R ⁹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ or -SR ^c ;
R ⁸ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or oxygen protecting group;
p is 0, 1, 2, or 3; and q is 0, 1, 2, 3, or 4.

In certain embodiments, the compound represented by formula (IV) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. It is.

In certain embodiments, the compound represented by formula (IV) has formula (IV-a):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; During the ceremony:
L ² is a linker containing 1 to 34 carbon atoms, including optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclyl and each R N is independently hydrogen, optionally substituted alkyl, or any combination thereof; and each R ^N is independently hydrogen, optionally substituted alkyl, or any combination thereof; , optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or nitrogen protecting group.

In certain embodiments, the compound represented by formula (IV-a) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (IV-a) is represented by formula (IV-b):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; During the ceremony:
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In certain embodiments, the compound represented by formula (IV-b) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (IV-b) is represented by formula (IV-c):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (IV) has formula (IV-d):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (IV-d) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (IV-a) is represented by formula (IV-e):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (IV-e) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (IV-b) is represented by formula (IV-f):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (IV-f) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (IV) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. It is.

Examples of compounds represented by formula (IV) include, but are not limited to, the following:
and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof.

Compound represented by formula (V) As generally described herein, a compound represented by formula (V) is a heterodimer composed of two monomers, where one The monomer of is JQ-1 or an analog thereof, and the other monomer is I-BET151 or an analog thereof. The monomers of the compound represented by formula (V) are linked through the 2-position of the JQ-1 or JQ-1-like monomer. Provided herein includes formula (V):
and their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs, During the ceremony:
L is a linker containing 1 to 40 carbon atoms, including optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene , optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene, or any combination thereof;
In any case, R ¹ , R ³ , and R ⁴ are independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted is substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ;
In each case, R ^a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or oxygen protecting group. is;
In each instance, R ^b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or nitrogen protecting group. or optionally two R ^3b are joined together with intervening atoms to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
In each case, R ^c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or sulfur protecting group. is;
R ⁵ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclylalkyl, is optionally substituted carbocyclylalkyl, optionally substituted acyl, -OR ^5a , or -N(R ^5b ) ₂ ;
In any case, R ^5a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaryl. is an alkyl, an optionally substituted heterocyclylalkyl, an optionally substituted carbocyclylalkyl, an optionally substituted acyl, or an oxygen protecting group;
In any case, R ^5b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaryl. alkyl, optionally substituted heterocyclylalkyl, optionally substituted carbocyclylalkyl, optionally substituted acyl, or nitrogen protecting group; or optionally two R ^3b are joined together with intervening atoms to form optionally substituted heterocyclyl or optionally substituted hetero form an aryl;
m in each case is independently 0, 1, 2, 3, 4, or 5;
In any case, R ⁶ , R ⁷ , R ¹⁰ , and R ¹¹ are independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted is carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ;
R ⁹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ or -SR ^c ;
R ⁸ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or oxygen protecting group;
p is 0, 1, 2, or 3; and q is 0, 1, 2, 3, or 4.

In certain embodiments, the compound represented by formula (V) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. It is.

In certain embodiments, the compound represented by formula (V) has formula (Va):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; During the ceremony:
L ² is a linker containing 1 to 34 carbon atoms, including optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclyl and each R N is independently hydrogen, optionally substituted alkyl, or any combination thereof; and each R ^N is independently hydrogen, optionally substituted alkyl , optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or nitrogen protecting group.

In certain embodiments, the compound represented by formula (Va) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In some embodiments, the compound represented by formula (V-a) has formula (V-b):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; During the ceremony:
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In certain embodiments, the compound represented by formula (Vb) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (Vb) has formula (Vc):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (Vb) is represented by formula (Vd):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (V) has formula (Ve):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (Ve) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In some embodiments, the compound represented by formula (Va) has formula (Vf):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (Vf) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (Vb) has formula (Vg):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (Vg) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (V) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. It is.

Examples of compounds represented by formula (IV) include, but are not limited to, the following:
and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof.

Compound represented by formula (VI) As generally described herein, a compound represented by formula (VI) is a homodimer composed of two monomers; mer is I-BET151 or an analog thereof. Provided herein includes formula (VI):
and their pharmaceutically acceptable salts, hydrates, solvates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs. , in the formula:
L is a linker containing 1 to 40 carbon atoms, including optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene , optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene, or any combination thereof;
In any case, R ⁶ , R ⁷ , R ¹⁰ , and R ¹¹ are independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted is carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ;
R ⁹ is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ or -SR ^c ;
In each case, R ^a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or oxygen protecting group. is;
In each instance, R ^b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or nitrogen protecting group. or optionally two R ^3b are joined together with intervening atoms to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
In any case, R ^c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or sulfur protecting group. is;
R ⁸ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or oxygen protecting group;
p is 0, 1, 2, or 3; and q is 0, 1, 2, 3, or 4.

In certain embodiments, the compound represented by formula (VI) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. It is.

In certain embodiments, the compound represented by formula (VI) has formula (VI-a):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; During the ceremony:
L ² is a linker containing 1 to 34 carbon atoms, including optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted carbocyclyl and each R N is independently hydrogen, optionally substituted alkyl, or any combination thereof; and each R ^N is independently hydrogen, optionally substituted alkyl , optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or nitrogen protecting group.

In certain embodiments, the compound represented by formula (VI-a) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (VI-a) is represented by formula (VI-b):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; During the ceremony:
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In certain embodiments, the compound represented by formula (VI-b) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (VI-b) is represented by formula (VI-c):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (VI) has formula (VI-d):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (VI-d) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (VI-a) is represented by formula (VI-e):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (VI-e) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (VI-b) is represented by formula (VI-f):
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, cocrystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (VI-f) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

In certain embodiments, the compound represented by formula (VI) has the following formula:
or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or protein of It's a drug.

Examples of compounds represented by formula (VI) include, but are not limited to, the following:
and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, cocrystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof.

Linkers L, L ¹ , and L ²
Compounds of formulas (I), (II), (III), (IV), (V), and (VI) include linkers represented by L, L ¹ , and L ² . As generally defined herein, L is a linker containing from 1 to 40 carbon atoms, including optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted selected from the group consisting of substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene, or any combination thereof. In certain embodiments, L contains 1-10 carbon atoms. In certain embodiments, L contains 1-20 carbon atoms. In certain embodiments, L contains 1-30 carbon atoms. In certain embodiments, L contains 10-40 carbon atoms. In certain embodiments, L contains 20-40 carbon atoms. In certain embodiments, L contains 30-40 carbon atoms. In certain embodiments, L includes optionally substituted alkylene. In certain embodiments, L includes optionally substituted heteroalkylene. In certain embodiments, L includes optionally substituted alkenylene. In certain embodiments, L includes optionally substituted heteroalkenylene. In certain embodiments, L includes optionally substituted alkynylene. In certain embodiments, L includes optionally substituted heteroalkynylene. In certain embodiments, L includes optionally substituted carbocyclylene. In certain embodiments, L includes optionally substituted heterocyclylene. In certain embodiments, L includes optionally substituted arylene. In certain embodiments, L includes an optionally substituted heteroarylene.

In certain embodiments, L is optionally substituted alkylene.
In certain embodiments, L is unsubstituted alkylene.

In certain embodiments, L is of the formula:
In the formula, s is an integer from 1 to 40 (inclusive).

In certain embodiments, L is optionally substituted heteroalkylene. In certain embodiments, L is substituted heteroalkylene. In certain embodiments, L is unsubstituted heteroalkylene. In certain embodiments, L is of the formula:
It is represented by one of the following.
In certain embodiments, L is an optionally substituted heteroalkylene containing one or more nitrogen atoms. In certain embodiments, L is an optionally substituted heteroalkylene containing one or more oxygen atoms. In certain embodiments, L is an optionally substituted heteroalkylene containing one or more nitrogen atoms and one or more oxygen atoms. In certain embodiments, L is a substituted heteroalkylene containing one or more esters (eg, -C(=O)O- or -OC(=O)-). In certain embodiments, L is a substituted heteroalkylene containing one or more amides (eg, -C(=O)N(R ^N )- or -N(R ^N )C(=O)-). In certain embodiments, L is of the formula:
It is represented by one of the following. In certain embodiments, L is of the formula:
It is represented by one of the following.

In certain embodiments, L is an optionally substituted heteroalkylene containing one or more ethers (eg, -O-). In some embodiments, L includes a polyether chain. In certain embodiments, L comprises polyethylene glycol (PEG chains). In certain embodiments, L is of the formula:
It is represented by one of the following.

In certain embodiments, L is a substituted heteroalkylene containing one or more amides and one or more ethers. In certain embodiments, L is substituted heteroalkylene including one or more esters and one or more ethers. In certain embodiments, L is of the formula:
It is represented by one of the following. In certain embodiments, L is of the formula:
It is represented by one of the following.

In certain embodiments, L is of the formula:
It is represented by one of the following.

In certain embodiments, L is of the formula:
It is represented by one of the following.

In certain embodiments, L includes a combination of an optionally substituted heteroalkylene and an optionally substituted heterocyclylene. For example, in some embodiments, L is of the formula:
It is represented by one of the following.

As generally defined herein, L ¹ is a linker containing from 1 to 36 carbon atoms, including optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, selected from the group consisting of optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene, or any combination thereof. In certain embodiments, L ¹ contains 1-10 carbon atoms. In certain embodiments, L ¹ contains 1-20 carbon atoms. In certain embodiments, L ¹ contains 1-30 carbon atoms. In certain embodiments, L ¹ contains 10-36 carbon atoms. In certain embodiments, L ¹ contains 20-36 carbon atoms. In certain embodiments, L ¹ includes optionally substituted alkylene. In certain embodiments, L ¹ includes optionally substituted heteroalkylene. In certain embodiments, L ¹ includes optionally substituted alkenylene. In certain embodiments, L ¹ includes an optionally substituted heteroalkenylene. In certain embodiments, L ¹ includes optionally substituted alkynylene. In certain embodiments, L ¹ includes an optionally substituted heteroalkynylene. In certain embodiments, L ¹ includes an optionally substituted carbocyclylene. In certain embodiments, L ¹ includes optionally substituted heterocyclylene. In certain embodiments, L ¹ includes an optionally substituted arylene. In certain embodiments, L ¹ includes an optionally substituted heteroarylene.

In certain embodiments, L ¹ is optionally substituted alkylene. In certain embodiments, L ¹ is unsubstituted alkylene. In some embodiments, L ¹ is of the formula:
In the formula, s is an integer from 1 to 36 (inclusive).

In certain embodiments, L ¹ is an optionally substituted heteroalkylene containing one or more nitrogen atoms. In certain embodiments, L ¹ is an optionally substituted heteroalkylene containing one or more oxygen atoms. In certain embodiments, L ¹ is an optionally substituted heteroalkylene containing one or more nitrogen atoms and one or more oxygen atoms. In certain embodiments, L ¹ is a substituted heteroalkylene containing one or more esters (eg, -C(=O)O- or -OC(=O)-). In certain embodiments, L ¹ is a substituted heteroalkylene containing one or more amides (eg, -C(=O)N(R ^N )- or -N(R ^N )C(=O)-). In certain embodiments, L ¹ is of the formula:
It is represented by one of the following. In certain embodiments, L ¹ is of the formula:
It is represented by one of the following.

In certain embodiments, L ¹ is an optionally substituted heteroalkylene containing one or more ethers (eg, -O-). In some embodiments, L ¹ includes a polyether chain. In certain embodiments, L ¹ comprises polyethylene glycol (PEG chains). In certain embodiments, L ¹ is of the formula:
It is represented by one of the following.

In certain embodiments, L ¹ is a substituted heteroalkylene containing one or more amides and one or more ethers. In certain embodiments, L ¹ is a substituted heteroalkylene that includes one or more esters and one or more ethers. In certain embodiments, L ¹ is a substituted heteroalkylene containing one or more amides and one or more ethers. In certain embodiments, L ¹ is of the formula:
It is represented by one of the following. In certain embodiments, L ¹ is of the formula:
It is represented by one of the following. In certain embodiments, L ¹ is of the formula:
It is represented by one of the following. In certain embodiments, L ¹ is of the formula:
It is represented by one of the following.

In certain embodiments, L ¹ includes a combination of an optionally substituted heteroalkylene and an optionally substituted heterocyclylene. For example, in some embodiments, L ¹ is of the formula:
It is represented by one of the following.

As generally defined herein, L ² is a linker containing 1 to 34 carbon atoms, including optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, selected from the group consisting of optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, and optionally substituted heteroarylene, or any combination thereof. In certain embodiments, L ² contains 1-10 carbon atoms. In certain embodiments, L ² contains 1-20 carbon atoms. In certain embodiments, L ² contains 1-34 carbon atoms. In certain embodiments, L ² contains 10-34 carbon atoms. In certain embodiments, L ² contains 10-34 carbon atoms. In certain embodiments, L ² contains 30-34 carbon atoms. In certain embodiments, L ² includes optionally substituted alkylene. In certain embodiments, L ² includes optionally substituted heteroalkylene. In certain embodiments, L ² includes optionally substituted alkenylene. In certain embodiments, L ² comprises an optionally substituted heteroalkenylene. In certain embodiments, L ² includes optionally substituted alkynylene. In certain embodiments, L ² comprises an optionally substituted heteroalkynylene. In certain embodiments, L ² comprises an optionally substituted carbocyclylene. In certain embodiments, L ² comprises an optionally substituted heterocyclylene. In certain embodiments, L ² includes an optionally substituted arylene. In certain embodiments, L ² includes an optionally substituted heteroarylene.

In certain embodiments, L ² is optionally substituted alkylene. In certain embodiments, L ² is unsubstituted alkylene. In some embodiments, L ² is of the formula:
In the formula, s is an integer from 1 to 34 (inclusive).

In certain embodiments, L ² is substituted heteroalkylene. In certain embodiments, L ² is unsubstituted heteroalkylene. In certain embodiments, L ² is an optionally substituted heteroalkylene linker containing one or more oxygen atoms.
In certain embodiments, L ² is an unsubstituted heteroalkylene linker containing one or more oxygen atoms. In certain embodiments, L ² is an optionally substituted heteroalkylene linker containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 oxygen atoms. In certain embodiments, L ² is an unsubstituted heteroalkylene linker containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 oxygen atoms. In certain embodiments, L ² is an optionally substituted polyether linker. In certain embodiments, L ² is an unsubstituted polyether linker. In certain embodiments, L ² is an optionally substituted polyethylene glycol (PEG) linker. In certain embodiments, L ² is an unsubstituted polyethylene glycol (PEG) linker. In some embodiments, L ² is of the formula:
It is represented by one of the following. In some embodiments, L ² is of the formula:
It is represented by one of the following.

As generally defined herein, n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, n is 7. In certain embodiments, n is 8. In certain embodiments, n is 9. In certain embodiments, n is 10.

Group R ¹
Formulas (I), (II), (III), (IV) and (V) include the radical R ¹ . As generally defined herein, each occurrence of R ¹ is independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ; where R ^a , R ^b , and R ^c are , as defined herein. In certain embodiments, at least one occurrence of R ¹ is hydrogen. In certain embodiments, at least one occurrence of R ¹ is halogen. In certain embodiments, at least one occurrence of R ¹ is -CN. In certain embodiments, at least one occurrence of R ¹ is -NO ₂ . In certain embodiments, at least one occurrence of R ¹ is -N ₃ . In certain embodiments, at least one occurrence of R ¹ is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ¹ is optionally substituted alkenyl. In certain embodiments, at least one occurrence of R ¹ is optionally substituted alkynyl. In certain embodiments, at least one occurrence of R ¹ is optionally substituted carbocyclyl. In certain embodiments, at least one occurrence of R ¹ is optionally substituted heterocyclyl. In certain embodiments, at least one occurrence of R ¹ is optionally substituted aryl. In certain embodiments, at least one occurrence of R ¹ is optionally substituted heteroaryl. In certain embodiments, at least one occurrence of R ¹ is optionally substituted acyl. In certain embodiments, at least one occurrence of R ¹ is -OR ^a . In certain embodiments, at least one occurrence of R ¹ is -N(R ^b ) ₂ . In certain embodiments, at least one occurrence of R ¹ is -SR ^c . In certain embodiments, at least one occurrence of R ¹ is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ¹ is optionally substituted C _1-6 alkyl. In certain embodiments, at least one occurrence of R ¹ is unsubstituted C _1-6 alkyl. In certain embodiments, at least one occurrence of R ¹ is optionally substituted C _1-3 alkyl. In certain embodiments, at least one occurrence of R ¹ is unsubstituted C _1-3 alkyl. In certain embodiments, at least one occurrence of R ¹ is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, at least one occurrence of R ¹ is methyl. In certain embodiments, any occurrence of R ¹ is methyl. In certain embodiments, when a formula includes two R ¹ groups, the two R ¹ groups can be the same or different.

Group R ²
Formulas (I), (II), and (IV) include the group ^R2 . As generally defined herein, R ² in any occurrence is independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ; where R ^a , R ^b , and R ^c are , as defined herein. In certain embodiments, at least one occurrence of ^R2 is hydrogen. In certain embodiments, at least one occurrence of ^R2 is halogen. In certain embodiments, at least one occurrence of R ² is -CN. In certain embodiments, at least one occurrence of R ² is -NO ₂ . In certain embodiments, at least one occurrence of R ² is -N ₃ . In certain embodiments, at least one occurrence of R ² is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ² is optionally substituted alkenyl. In certain embodiments, at least one occurrence of R ² is optionally substituted alkynyl. In certain embodiments, at least one occurrence of R ² is optionally substituted carbocyclyl. In certain embodiments, at least one occurrence of R ² is optionally substituted heterocyclyl. In certain embodiments, at least one occurrence of R ² is optionally substituted aryl. In certain embodiments, at least one occurrence of R ² is optionally substituted heteroaryl. In certain embodiments, at least one occurrence of R ² is optionally substituted acyl. In certain embodiments, at least one occurrence of R ² is -OR ^a . In certain embodiments, at least one occurrence of R ² is -N(R ^b ) ₂ . In certain embodiments, at least one occurrence of R ² is -SR ^c . In certain embodiments, at least one occurrence of R ² is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ² is optionally substituted C _1-6 alkyl. In certain embodiments, at least one occurrence of R ² is unsubstituted C _1-6 alkyl. In certain embodiments, at least one occurrence of R ² is optionally substituted C _1-3 alkyl. In certain embodiments, at least one occurrence of R ² is unsubstituted C _1-3 alkyl. In certain embodiments, at least one occurrence of R ² is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, at least one occurrence of ^R2 is methyl. In certain embodiments, any occurrence of R ² is methyl. In certain embodiments, when a formula includes two R ² groups, the groups may be the same or different.

Group R ³
Formulas (I), (II), (III), (IV) and (V) include the group ^R3 . As generally defined herein, R ³ at any occurrence is independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ; where R ^a , R ^b , and R ^c are , as defined herein. In certain embodiments, at least one occurrence of ^R3 is hydrogen. In certain embodiments, at least one occurrence of ^R3 is halogen. In certain embodiments, at least one occurrence of R ³ is -CN. In certain embodiments, at least one occurrence of R ³ is -NO ₂ . In certain embodiments, at least one occurrence of R ³ is -N ₃ . In certain embodiments, at least one occurrence of R ³ is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ³ is optionally substituted alkenyl. In certain embodiments, at least one occurrence of R ³ is optionally substituted alkynyl. In certain embodiments, at least one occurrence of R ³ is optionally substituted carbocyclyl. In certain embodiments, at least one occurrence of R ³ is optionally substituted heterocyclyl. In certain embodiments, at least one occurrence of R ³ is optionally substituted aryl. In certain embodiments, at least one occurrence of R ³ is optionally substituted heteroaryl. In certain embodiments, at least one occurrence of R ³ is optionally substituted acyl. In certain embodiments, at least one occurrence of R ³ is -OR ^a . In certain embodiments, at least one occurrence of R ³ is -N(R ^b ) ₂ . In certain embodiments, at least one occurrence of R ³ is -SR ^c . In certain embodiments, at least one occurrence of R ³ is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ³ is optionally substituted C _1-6 alkyl. In certain embodiments, at least one occurrence of R ³ is unsubstituted C _1-6 alkyl. In certain embodiments, at least one occurrence of R ³ is optionally substituted C _1-3 alkyl. In certain embodiments, at least one occurrence of R ³ is unsubstituted C _1-3 alkyl. In certain embodiments, at least one occurrence of R ³ is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, at least one occurrence of R ³ is methyl. In certain embodiments, any occurrence of R ³ is methyl. In certain embodiments, when a formula includes two ^R groups, the groups may be the same or different.

Groups R ⁴ and m
Formulas (I), (II), (III), (IV) and (V) include the group R ⁴ . As generally defined herein, R ⁴ in any occurrence is independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ; where R ^a , R ^b , and R ^c are , as defined herein. In certain embodiments, at least one occurrence of R ⁴ is hydrogen. In certain embodiments, at least one occurrence of R ⁴ is halogen. In certain embodiments, at least one occurrence of R ⁴ is -CN. In certain embodiments, at least one occurrence of R ⁴ is -NO ₂ . In certain embodiments, at least one occurrence of R ⁴ is -N ₃ . In certain embodiments, at least one occurrence of R ⁴ is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ⁴ is optionally substituted alkenyl. In certain embodiments, at least one occurrence of R ⁴ is optionally substituted alkynyl. In certain embodiments, at least one occurrence of R ⁴ is optionally substituted carbocyclyl. In certain embodiments, at least one occurrence of R ⁴ is optionally substituted heterocyclyl. In certain embodiments, at least one occurrence of R ⁴ is optionally substituted aryl. In certain embodiments, at least one occurrence of R ⁴ is optionally substituted heteroaryl. In certain embodiments, at least one occurrence of R ⁴ is optionally substituted acyl. In certain embodiments, at least one occurrence of R ⁴ is -OR ^a . In certain embodiments, at least one occurrence of R ⁴ is -N(R ^b ) ₂ . In certain embodiments, at least one occurrence of R ⁴ is -SR ^c . In certain embodiments, at least one occurrence of R ⁴ is halogen. In certain embodiments, at least one occurrence of R ⁴ is -Cl, -Br, -F, or -I. In certain embodiments, at least one occurrence of R ⁴ is -Cl. In certain embodiments, at least one occurrence of R ⁴ is -Br. In certain embodiments, at least one occurrence of R ⁴ is -F. In certain embodiments, at least one occurrence of R ⁴ is -I.

In certain embodiments, m is 1; and R ⁴ is the point of attachment of the diazepine ring to the benzenoid ring in the para position. In certain embodiments, m is 1; and R ⁴ is halogen (eg, -Cl, -Br, -F, or -I). In certain embodiments, m is 1; R ⁴ is halogen (eg, -Cl, -Br, -F, or -I); and R ⁴ is such that the point of attachment of the diazepine ring to the benzenoid ring is It is in para position. In certain embodiments, m is 1 and R ⁴ is -Cl. In certain embodiments, m is 1 and R ⁴ is -Cl; and R ⁴ is in the para position of the point of attachment to the benzenoid ring of the diazepine ring. In certain embodiments, m is 1; and R ⁴ is -CN. In certain embodiments, m is 1; R ⁴ is -CN; and R ⁴ is the point of attachment of the diazepine ring to the benzenoid ring in the para position.

As generally defined herein, m in each case is independently 0, 1, 2, 3, 4, or 5. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5.

Group R ⁵
Formulas (I), (III), and (V) include the group R ⁵ . As generally defined herein, R ⁵ is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted substituted heteroarylalkyl, optionally substituted heterocyclylalkyl, optionally substituted carbocyclylalkyl, optionally substituted acyl, -OR ^5a , or -N(R ^5b ) ₂ . In certain embodiments, R ⁵ is hydrogen. In certain embodiments, R ⁵ is optionally substituted alkyl. In certain embodiments, R ⁵ is optionally substituted alkenyl. In certain embodiments, R ⁵ is optionally substituted alkynyl. In certain embodiments, R ⁵ is optionally substituted carbocyclyl. In certain embodiments, R ⁵ is optionally substituted heterocyclyl. In certain embodiments, R ⁵ is optionally substituted aryl. In certain embodiments, R ⁵ is optionally substituted heteroaryl. In certain embodiments, R ⁵ is optionally substituted aralkyl. In certain embodiments, R ⁵ is optionally substituted heteroarylalkyl. In certain embodiments, R ⁵ is optionally substituted heterocyclylalkyl. In certain embodiments, R ⁵ is optionally substituted carbocyclylalkyl. In certain embodiments, R ⁵ is optionally substituted acyl.

In certain embodiments, R ⁵ is -OR ^5a . In certain embodiments, R ⁵ is -OR ^5a ; and R ^5a is optionally substituted alkyl. In certain embodiments, R ⁵ is -OR ^5a ; and R ^5a is optionally substituted C _1-6 alkyl. In certain embodiments, R ⁵ is -OR ^5a ; and R ^5a is unsubstituted C _1-6 alkyl. In certain embodiments, R ⁵ is -OR ^5a ; and R ^5a is optionally substituted C _1-3 alkyl. In certain embodiments, R ⁵ is -OR ^5a ; and R ^5a is unsubstituted C _1-3 alkyl. In certain embodiments, R ⁵ is -OR ^5a ; and R ^5a is the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. selected from. In certain embodiments, R ⁵ is -OR ^5a ; and R ^5a is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and sec-butyl. . In certain embodiments, R ⁵ is -OR ^5a ; and R ^5a is selected from the group consisting of methyl, ethyl, n-propyl, and iso-propyl. In certain embodiments, R ⁵ is -OR ^5a ; and R ^5a is methyl. In certain embodiments, R ⁵ is -OCH ₃ .

In certain embodiments, R ⁵ is -N(R ^5b ) ₂ . In certain embodiments, R ⁵ is -N(R ^5b ) ₂ ; and at least one occurrence of R ^5b is hydrogen. In certain embodiments, R ⁵ is -N(R ^5b ) ₂ ; and at least one occurrence of R ^5b is optionally substituted alkyl. In certain embodiments, R ⁵ is -N(R ^5b ) ₂ ; and at least one occurrence of R ^5b is optionally substituted C _1-6 alkyl. In certain embodiments, R ⁵ is -N(R ^5b ) ₂ ; and at least one occurrence of R ^5b is unsubstituted C _1-6 alkyl. In certain embodiments, R ⁵ is -N(R ^5b ) ₂ ; and at least one occurrence of R ^5b is substituted C _1-6 alkyl. In certain embodiments, R ⁵ is -N(R ^5b ) ₂ ; and at least one occurrence of R ^5b is optionally substituted C _1-3 alkyl. In certain embodiments, R ⁵ is -N(R ^5b ) ₂ ; and at least one occurrence of R ^5b is unsubstituted C _1-3 alkyl. In certain embodiments, R ⁵ is -N(R ^5b ) ₂ ; and at least one occurrence of R ^5b is substituted C _1-3 alkyl. In certain embodiments, R ⁵ is -N(R ^5b ) ₂ ; and at least one occurrence of R ^5b is C _1-3 alkyl substituted with one occurrence of -OH. In certain embodiments, R ⁵ is -N(R ^5b ) ₂ ; and at least one occurrence of R ^5b is -CH ₂ CH ₂ OH. In certain embodiments, R ⁵ is of the formula:
It is expressed as In certain embodiments, R ⁵ is of the formula:
It is expressed as In some embodiments, R ⁵ is -N(R ^5b ) ₂ ; and at least one occurrence of R ^5b is optionally substituted heterocyclylalkyl. In certain embodiments, R ⁵ is -N(R ^5b ) ₂ ; and at least one occurrence of R ^5b is optionally substituted -C _1-6 alkyl-heterocyclyl. In certain embodiments, R ⁵ is -N(R ^5b ) ₂ ; and at least one occurrence of R ^5b is optionally substituted -C _1-6 alkyl-piperazinyl. In certain embodiments, R ⁵ is -N(R ^5b ) ₂ ; and at least one occurrence of R ^5b is optionally substituted -C _1-3 alkyl-heterocyclyl. In certain embodiments, R ⁵ is -N(R ^5b ) ₂ ; and at least one occurrence of R ^5b is optionally substituted -C _1-3 alkyl-piperazinyl. In certain embodiments, R ⁵ is -N(R ^5b ) ₂ ; and at least one occurrence of R ^5b is an optionally substituted -CH ₂ CH ₂ CH ₂ -piperazinyl. In certain embodiments, R ⁵ is -N(R ^5b ) ₂ ; and at least one occurrence of R ^5b is substituted -CH ₂ CH ₂ CH ₂ -piperazinyl. In certain embodiments, R ⁵ is of the formula:
It is expressed as In certain embodiments, R ⁵ is of the formula:
It is expressed as

As generally defined herein, each occurrence of R ^5a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted hetero Aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclylalkyl, optionally substituted carbocyclylalkyl, optionally substituted acyl, or oxygen protecting group. In certain embodiments, R ^5a is hydrogen. In certain embodiments, R ^5a is optionally substituted alkyl. In certain embodiments, R ^5a is optionally substituted alkenyl. In certain embodiments, R ^5a is optionally substituted alkynyl. In certain embodiments, R ^5a is optionally substituted carbocyclyl. In certain embodiments, R ^5a is optionally substituted heterocyclyl. In certain embodiments, R ^5a is optionally substituted aryl. In certain embodiments, R ^5a is optionally substituted heteroaryl. In certain embodiments, R ^5a is optionally substituted aralkyl. In certain embodiments, R ^5a is optionally substituted heteroarylalkyl. In certain embodiments, R ^5a is optionally substituted heterocyclylalkyl. In certain embodiments, R ^5a is optionally substituted carbocyclylalkyl. In certain embodiments, R ^5a is optionally substituted acyl. In certain embodiments, R ^5a is an oxygen protecting group. In certain embodiments, R ^5a is optionally substituted alkyl. In certain embodiments, R ^5a is optionally substituted C _1-6 alkyl. In certain embodiments, R ^5a is unsubstituted C _1-6 alkyl. In certain embodiments, R ^5a is optionally substituted C _1-3 alkyl. In certain embodiments, R ^5a is unsubstituted C _1-3 alkyl. In certain embodiments, R ^5a is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R ^5a is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and sec-butyl. In certain embodiments, R ^5a is selected from the group consisting of methyl, ethyl, n-propyl, and iso-propyl. In certain embodiments, R ^5a is methyl. In certain embodiments, R ^5a is not tert-butyl. In certain embodiments, R ^5a is not tert-butyl, iso-butyl, or sec-butyl.

As generally defined herein, each occurrence of R ^5b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted hetero is aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclylalkyl, optionally substituted carbocyclylalkyl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R ^5b are joined together with intervening atoms. Together, they form an optionally substituted heterocyclyl or an optionally substituted heteroaryl. In certain embodiments, at least one occurrence of R ^5b is hydrogen. In certain embodiments, at least one occurrence of R ^5b is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ^5b is optionally substituted alkenyl. In certain embodiments, at least one occurrence of R ^5b is optionally substituted alkynyl. In certain embodiments, at least one occurrence of R ^5b is optionally substituted carbocyclyl. In certain embodiments, at least one occurrence of R ^5b is optionally substituted heterocyclyl. In certain embodiments, at least one occurrence of R ^5b is optionally substituted aryl. In certain embodiments, at least one occurrence of R ^5b is optionally substituted heteroaryl. In certain embodiments, at least one occurrence of R ^5b is optionally substituted aralkyl. In certain embodiments, at least one occurrence of R ^5b is optionally substituted heteroarylalkyl. In certain embodiments, at least one occurrence of R ^5b is optionally substituted heterocyclylalkyl. In certain embodiments, at least one occurrence of R ^5b is optionally substituted carbocyclylalkyl. In certain embodiments, at least one occurrence of R ^5b is optionally substituted acyl. In certain embodiments, at least one occurrence of R ^5b is a nitrogen protecting group. In certain embodiments, two R ^5b are joined together with intervening atoms to form an optionally substituted heterocyclyl. In certain embodiments, two R ^5b are joined together with the intervening atoms to form an optionally substituted heteroaryl. In certain embodiments, two R ^5b 's attached to the same nitrogen atom are joined together with an intervening atom to form an optionally substituted heterocyclyl. In certain embodiments, two R ^5b 's attached to the same nitrogen atom are joined together with an intervening atom to form an optionally substituted heteroaryl.

In certain embodiments, when a formula includes two R ⁵ groups, the two R ⁵ groups can be the same or different.

Group R ⁶
Formulas (V) and (VI) include the group ^R6 . As generally defined herein, R ⁶ in any occurrence is independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ; where R ^a , R ^b , and R ^c are , as defined herein. In certain embodiments, at least one occurrence of R ⁶ is hydrogen. In certain embodiments, at least one occurrence of R ⁶ is halogen. In certain embodiments, at least one occurrence of R ⁶ is -CN. In certain embodiments, at least one occurrence of R ⁶ is -NO ₂ . In certain embodiments, at least one occurrence of R ⁶ is -N ₃ . In certain embodiments, at least one occurrence of R ⁶ is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ⁶ is optionally substituted alkenyl. In certain embodiments, at least one occurrence of R ⁶ is optionally substituted alkynyl. In certain embodiments, at least one occurrence of R ⁶ is optionally substituted carbocyclyl. In certain embodiments, at least one occurrence of R ⁶ is optionally substituted heterocyclyl. In certain embodiments, at least one occurrence of R ⁶ is optionally substituted aryl. In certain embodiments, at least one occurrence of R ⁶ is optionally substituted heteroaryl. In certain embodiments, at least one occurrence of R ⁶ is optionally substituted acyl. In certain embodiments, at least one occurrence of R ⁶ is -OR ^a . In certain embodiments, at least one occurrence of R ⁶ is -N(R ^b ) ₂ . In certain embodiments, at least one occurrence of R ⁶ is -SR ^c . In certain embodiments, at least one occurrence of R ⁶ is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ⁶ is optionally substituted C _1-6 alkyl. In certain embodiments, at least one occurrence of R ⁶ is unsubstituted C _1-6 alkyl. In certain embodiments, at least one occurrence of R ⁶ is optionally substituted C _1-3 alkyl. In certain embodiments, at least one occurrence of R ⁶ is unsubstituted C _1-3 alkyl. In certain embodiments, at least one occurrence of R ⁶ is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, at least one occurrence of R ⁶ is methyl. In certain embodiments, any occurrence of R ⁶ is methyl. In certain embodiments, when a formula includes two R ⁶ groups, the groups can be the same or different.

Group R ⁷
Formulas (V) and (VI) include the group R ⁷ . As generally defined herein, R ⁷ at any occurrence is independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ; where R ^a , R ^b , and R ^c are , as defined herein. In certain embodiments, at least one occurrence of R ⁷ is hydrogen. In certain embodiments, at least one occurrence of R ⁷ is halogen. In certain embodiments, at least one occurrence of R ⁷ is -CN. In certain embodiments, at least one occurrence of R ⁷ is -NO ₂ . In certain embodiments, at least one occurrence of R ⁷ is -N ₃ . In certain embodiments, at least one occurrence of R ⁷ is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ⁷ is optionally substituted alkenyl. In certain embodiments, at least one occurrence of R ⁷ is optionally substituted alkynyl. In certain embodiments, at least one occurrence of R ⁷ is optionally substituted carbocyclyl. In certain embodiments, at least one occurrence of R ⁷ is optionally substituted heterocyclyl. In certain embodiments, at least one occurrence of R ⁷ is optionally substituted aryl. In certain embodiments, at least one occurrence of R ⁷ is optionally substituted heteroaryl. In certain embodiments, at least one occurrence of R ⁷ is optionally substituted acyl. In certain embodiments, at least one occurrence of R ⁷ is -OR ^a . In certain embodiments, at least one occurrence of R ⁷ is -N(R ^b ) ₂ . In certain embodiments, at least one occurrence of R ⁷ is -SR ^c . In certain embodiments, at least one occurrence of R ⁷ is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ⁷ is optionally substituted C _1-6 alkyl. In certain embodiments, at least one occurrence of R ⁷ is unsubstituted C _1-6 alkyl. In certain embodiments, at least one occurrence of R ⁷ is optionally substituted C _1-3 alkyl. In certain embodiments, at least one occurrence of R ⁷ is unsubstituted C _1-3 alkyl. In certain embodiments, at least one occurrence of R ⁷ is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, at least one occurrence of R ⁷ is methyl. In certain embodiments, any occurrence of R ⁷ is methyl. In certain embodiments, when a formula includes two R ⁷ groups, the groups can be the same or different.

Group R ⁸
Formulas (V) and (VI) include the group ^R8 . As generally defined herein, R ⁸ at any occurrence is independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ; where R ^a , R ^b , and R ^c are , as defined herein. In certain embodiments, at least one occurrence of R ⁸ is hydrogen. In certain embodiments, at least one occurrence of R ⁸ is halogen. In certain embodiments, at least one occurrence of R ⁸ is -CN. In certain embodiments, at least one occurrence of R ⁸ is -NO ₂ . In certain embodiments, at least one occurrence of R ⁸ is -N ₃ . In certain embodiments, at least one occurrence of R ⁸ is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ⁸ is optionally substituted alkenyl. In certain embodiments, at least one occurrence of R ⁸ is optionally substituted alkynyl. In certain embodiments, at least one occurrence of R ⁸ is optionally substituted carbocyclyl. In certain embodiments, at least one occurrence of R ⁸ is optionally substituted heterocyclyl. In certain embodiments, at least one occurrence of R ⁸ is optionally substituted aryl. In certain embodiments, at least one occurrence of R ⁸ is optionally substituted heteroaryl. In certain embodiments, at least one occurrence of R ⁸ is optionally substituted acyl. In certain embodiments, at least one occurrence of R ⁸ is -OR ^a . In certain embodiments, at least one occurrence of R ⁸ is -N(R ^b ) ₂ . In certain embodiments, at least one occurrence of R ⁸ is -SR ^c . In certain embodiments, at least one occurrence of R ⁸ is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ⁸ is optionally substituted C _1-6 alkyl. In certain embodiments, at least one occurrence of R ⁸ is unsubstituted C _1-6 alkyl. In certain embodiments, at least one occurrence of R ⁸ is optionally substituted C _1-3 alkyl. In certain embodiments, at least one occurrence of R ⁸ is unsubstituted C _1-3 alkyl. In certain embodiments, at least one occurrence of R ⁸ is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, at least one occurrence of R ⁸ is methyl. In certain embodiments, any occurrence of R ⁸ is methyl. In certain embodiments, when a formula includes two R ⁸ groups, the groups may be the same or different.

Group R ⁹
Formulas (V) and (VI) include the group R ⁹ . As generally defined herein, R ⁹ at any occurrence is independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ; where R ^a , R ^b , and R ^c are , as defined herein. In certain embodiments, at least one occurrence of R ⁹ is hydrogen. In certain embodiments, at least one occurrence of R ⁹ is halogen. In certain embodiments, at least one occurrence of R ⁹ is -CN. In certain embodiments, at least one occurrence of R ⁹ is -NO ₂ . In certain embodiments, at least one occurrence of R ⁹ is -N ₃ . In certain embodiments, at least one occurrence of R ⁹ is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ⁹ is optionally substituted alkenyl. In certain embodiments, at least one occurrence of R ⁹ is optionally substituted alkynyl. In certain embodiments, at least one occurrence of R ⁹ is optionally substituted carbocyclyl. In certain embodiments, at least one occurrence of R ⁹ is optionally substituted heterocyclyl. In certain embodiments, at least one occurrence of R ⁹ is optionally substituted aryl. In certain embodiments, at least one occurrence of R ⁹ is optionally substituted heteroaryl. In certain embodiments, at least one occurrence of R ⁹ is optionally substituted acyl. In certain embodiments, at least one occurrence of R ⁹ is -OR ^a . In certain embodiments, at least one occurrence of R ⁹ is -N(R ^b ) ₂ . In certain embodiments, at least one occurrence of R ⁹ is -SR ^c . In certain embodiments, at least one occurrence of R ⁹ is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ⁹ is optionally substituted C _1-6 alkyl. In certain embodiments, at least one occurrence of R ⁹ is unsubstituted C _1-6 alkyl. In certain embodiments, at least one occurrence of R ⁹ is optionally substituted C _1-3 alkyl. In certain embodiments, at least one occurrence of R ⁹ is unsubstituted C _1-3 alkyl. In certain embodiments, at least one occurrence of R ⁹ is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, at least one occurrence of R ⁹ is methyl. In certain embodiments, any occurrence of R ⁹ is methyl. In certain embodiments, when a formula includes two R ⁹ groups, the groups can be the same or different.

Groups R ¹⁰ and p
Formulas (V) and (VI) include the group R ¹⁰ . As generally defined herein, R ¹⁰ in any occurrence is independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ; where R ^a , R ^b , and R ^c are , as defined herein. In certain embodiments, at least one occurrence of R ¹⁰ is hydrogen. In certain embodiments, at least one occurrence of R ¹⁰ is halogen. In certain embodiments, at least one occurrence of R ¹⁰ is -CN. In certain embodiments, at least one occurrence of R ¹⁰ is -NO ₂ . In certain embodiments, at least one occurrence of R ¹⁰ is -N ₃ . In certain embodiments, at least one occurrence of R ¹⁰ is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ¹⁰ is optionally substituted alkenyl. In certain embodiments, at least one occurrence of R ¹⁰ is optionally substituted alkynyl. In certain embodiments, at least one occurrence of R ¹⁰ is optionally substituted carbocyclyl. In certain embodiments, at least one occurrence of R ¹⁰ is optionally substituted heterocyclyl. In certain embodiments, at least one occurrence of R ¹⁰ is optionally substituted aryl. In certain embodiments, at least one occurrence of R ¹⁰ is optionally substituted heteroaryl. In certain embodiments, at least one occurrence of R ¹⁰ is optionally substituted acyl. In certain embodiments, at least one occurrence of R ¹⁰ is -OR ^a . In certain embodiments, at least one occurrence of R ¹⁰ is -N(R ^b ) ₂ . In certain embodiments, at least one occurrence of R ¹⁰ is -SR ^c . In certain embodiments, at least one occurrence of R ¹⁰ is hydrogen. In certain embodiments, any occurrence of R ¹⁰ is hydrogen.

As generally defined herein, p is 0, 1, 2, or 3. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.

Groups R ¹¹ and q
Formulas (V) and (VI) include the group R ¹¹ . As generally defined herein, each occurrence of R ¹¹ is independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ; where R ^a , R ^b , and R ^c are , as defined herein. In certain embodiments, at least one occurrence of R ¹¹ is hydrogen. In certain embodiments, at least one occurrence of R ¹¹ is halogen. In certain embodiments, at least one occurrence of R ¹¹ is -CN. In certain embodiments, at least one occurrence of R ¹¹ is -NO ₂ . In certain embodiments, at least one occurrence of R ¹¹ is -N ₃ . In certain embodiments, at least one occurrence of R ¹¹ is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ¹¹ is optionally substituted alkenyl. In certain embodiments, at least one occurrence of R ¹¹ is optionally substituted alkynyl. In certain embodiments, at least one occurrence of R ¹¹ is optionally substituted carbocyclyl. In certain embodiments, at least one occurrence of R ¹¹ is optionally substituted heterocyclyl. In certain embodiments, at least one occurrence of R ¹¹ is optionally substituted aryl. In certain embodiments, at least one occurrence of R ¹¹ is optionally substituted heteroaryl. In certain embodiments, at least one occurrence of R ¹¹ is optionally substituted acyl. In certain embodiments, at least one occurrence of R ¹¹ is -OR ^a . In certain embodiments, at least one occurrence of R ¹¹ is -N(R ^b ) ₂ . In certain embodiments, at least one occurrence of R ¹¹ is -SR ^c . In certain embodiments, at least one occurrence of R ¹¹ is hydrogen. In certain embodiments, any occurrence of R ¹¹ is hydrogen.

As generally defined herein, q is 0, 1, 2, 3, or 4. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 4.

Groups R ^a , R ^b , and R ^c
As generally defined herein, each occurrence of R ^a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted hetero Aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclylalkyl, optionally substituted carbocyclylalkyl, optionally substituted acyl, or oxygen protecting group. In certain embodiments, R ^a is hydrogen. In certain embodiments, R ^a is optionally substituted alkyl. In certain embodiments, R ^a is optionally substituted alkenyl. In certain embodiments, R ^a is optionally substituted alkynyl. In certain embodiments, R ^a is optionally substituted carbocyclyl. In certain embodiments, R ^a is optionally substituted heterocyclyl. In certain embodiments, R ^a is optionally substituted aryl. In certain embodiments, R ^a is optionally substituted heteroaryl. In certain embodiments, R ^a is optionally substituted aralkyl. In certain embodiments, R ^a is optionally substituted heteroarylalkyl. In certain embodiments, R ^a is optionally substituted heterocyclylalkyl. In certain embodiments, R ^a is optionally substituted carbocyclylalkyl. In certain embodiments, R ^a is optionally substituted acyl. In certain embodiments, R ^a is an oxygen protecting group.

As generally defined herein, in any case R ^b is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted hetero is aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclylalkyl, optionally substituted carbocyclylalkyl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R ^b are joined together with intervening atoms. Together, they form an optionally substituted heterocyclyl or an optionally substituted heteroaryl. In certain embodiments, at least one occurrence of R ^b is hydrogen. In certain embodiments, at least one occurrence of R ^b is optionally substituted alkyl. In certain embodiments, at least one occurrence of R ^b is optionally substituted alkenyl. In certain embodiments, at least one occurrence of R ^b is optionally substituted alkynyl. In certain embodiments, at least one occurrence of R ^b is optionally substituted carbocyclyl. In certain embodiments, at least one occurrence of R ^b is optionally substituted heterocyclyl. In certain embodiments, at least one occurrence of R ^b is optionally substituted aryl. In certain embodiments, at least one occurrence of R ^b is optionally substituted heteroaryl. In certain embodiments, at least one occurrence of R ^b is optionally substituted aralkyl. In certain embodiments, at least one occurrence of R ^b is optionally substituted heteroarylalkyl. In certain embodiments, at least one occurrence of R ^b is optionally substituted heterocyclylalkyl. In certain embodiments, at least one occurrence of R ^b is optionally substituted carbocyclylalkyl. In certain embodiments, at least one occurrence of R ^b is optionally substituted acyl. In certain embodiments, at least one occurrence of R ^b is a nitrogen protecting group. In certain embodiments, two R ^b are joined together with intervening atoms to form an optionally substituted heterocyclyl. In certain embodiments, two R ^b are joined together with intervening atoms to form an optionally substituted heteroaryl. In certain embodiments, two R ^b 's attached to the same nitrogen atom are joined together with intervening atoms to form an optionally substituted heterocyclyl. In certain embodiments, two R ^b 's attached to the same nitrogen atom are joined together with intervening atoms to form an optionally substituted heteroaryl.

As generally defined herein, in any case R ^c is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted hetero Aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted heterocyclylalkyl, optionally substituted carbocyclylalkyl, optionally substituted acyl, or sulfur protecting group. In certain embodiments, R ^c is hydrogen. In certain embodiments, R ^c is optionally substituted alkyl. In certain embodiments, R ^c is optionally substituted alkenyl. In certain embodiments, R ^c is optionally substituted alkynyl. In certain embodiments, R ^c is optionally substituted carbocyclyl. In certain embodiments, R ^c is optionally substituted heterocyclyl. In certain embodiments, R ^c is optionally substituted aryl. In certain embodiments, R ^c is optionally substituted heteroaryl. In certain embodiments, R ^c is optionally substituted aralkyl. In certain embodiments, R ^c is optionally substituted heteroarylalkyl. In certain embodiments, R ^c is optionally substituted heterocyclylalkyl. In certain embodiments, R ^c is optionally substituted carbocyclylalkyl. In certain embodiments, R ^c is optionally substituted acyl. In certain embodiments, R ^c is a sulfur protecting group.

PHARMACEUTICAL COMPOSITIONS, KITS, AND ADMINISTRATION The present disclosure describes the use of compounds described herein (e.g., represented by formula (I), (II), (III), (IV), (V), or (VI)). or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof), and optionally Pharmaceutical compositions are provided that include pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical compositions described herein contain a compound represented by formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutical composition thereof. and optionally pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical compositions described herein contain a compound represented by formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutical composition thereof. and pharmaceutically acceptable excipients.

In certain embodiments, a compound described herein is provided in an effective amount in a pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, an effective amount is an amount effective to treat and/or prevent a disease (eg, a disease described herein) in a subject in need thereof. In certain embodiments, an effective amount is an amount effective to treat a disease in a subject in need thereof. In certain embodiments, an effective amount is an amount effective to prevent disease in a subject in need thereof. In certain embodiments, an effective amount is an amount effective to reduce the risk of developing a disease in a subject in need thereof. In certain embodiments, an effective amount is an amount effective to provide male contraception in a subject in need thereof (eg, effective to inhibit spermatogenesis). In certain embodiments, an effective amount is an amount effective to inhibit viral replication. In certain embodiments, an effective amount is an amount effective to kill the virus. In certain embodiments, an effective amount is an amount effective to inhibit activity (eg, abnormal activity, such as increased activity or undesired activity) of a bromodomain-containing protein in a subject or cell. In certain embodiments, an effective amount is an amount effective to inhibit activity (eg, abnormal activity, such as increased or undesired activity) of the bromodomain in a subject or cell. In certain embodiments, an effective amount is an amount effective to inhibit binding of a bromodomain of a bromodomain-containing protein to an acetyl-lysine residue of a second protein (e.g., a histone) in a subject or cell. . In certain embodiments, an effective amount is an amount effective to modulate (eg, inhibit) transcriptional elongation in a subject or cell. In certain embodiments, an effective amount is an amount effective to modulate (e.g., downregulate or inhibit) the expression (e.g., transcription) of a gene regulated by a bromodomain-containing protein in a subject or cell. . In certain embodiments, an effective amount is an amount effective to induce apoptosis of cells. In certain embodiments, an effective amount is an amount effective to induce apoptosis in a subject. In certain embodiments, an effective amount is an amount effective to induce G1 phase arrest in a subject or cell. The effective amount of the compound may vary from about 0.001 mg/kg to about 1000 mg/kg (depending on the mode of administration) in one or more doses administered over one or several days. In certain embodiments, the effective amount per dose is from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 0.1 mg/kg to about 500 mg/kg, It varies from about 1.0 mg/kg to about 250 mg/kg, and from about 10.0 mg/kg to about 150 mg/kg.

In certain embodiments, the effective amount is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98% of the activity of the bromodomain-containing protein, the activity of the bromodomain, the bromodomain of the bromodomain-containing protein, the acetyl-lysine residue of a second protein (e.g., a histone) to inhibit binding to, transcription elongation, and/or expression (e.g., transcription) of genes regulated by bromodomain-containing proteins, to induce or increase apoptosis, or to induce or increase G1 phase arrest. This is an effective amount to In certain embodiments, the effective amount is determined by the activity of the bromodomain-containing protein, the binding of the bromodomain of the bromodomain-containing protein to an acetyl-lysine residue of a second protein (e.g., a histone), and/or the bromodomain-containing protein. The expression of the regulated gene (for example, transcription) can be reduced by up to about 90%, up to about 80%, up to about 70%, up to about 60%, up to about 50%, up to about 40%, An amount effective to inhibit up to about 30%, up to about 20%, or up to about 10%. Combinations of the ranges described herein (eg, at least about 20% and up to about 50%) are also within the scope of this disclosure. In some embodiments, the activity of the bromodomain-containing protein, the binding of the bromodomain of the bromodomain-containing protein to an acetyl-lysine residue of a second protein (e.g., a histone), and/or the gene regulated by the bromodomain-containing protein. The expression (eg, transcription) of is inhibited by an effective amount of a compound described herein by a percentage or range of percentages described herein.

In certain embodiments, the gene regulated by a bromodomain-containing protein is a gene regulated by a bromo and specific end (BET) protein. In certain embodiments, the gene regulated by the bromodomain-containing protein is BRD2. In certain embodiments, the gene regulated by the bromodomain-containing protein is BRD2(1). In certain embodiments, the gene regulated by the bromodomain-containing protein is BRD2 (2). In certain embodiments, the gene regulated by the bromodomain-containing protein is BRD3. In certain embodiments, the gene regulated by the bromodomain-containing protein is BRD3(1). In certain embodiments, the gene regulated by the bromodomain-containing protein is BRD3(2). In certain embodiments, the gene regulated by the bromodomain-containing protein is BRD4. In certain embodiments, the gene regulated by the bromodomain-containing protein is BRD4(1). In certain embodiments, the gene regulated by the bromodomain-containing protein is BRD4(2). In certain embodiments, the gene regulated by the bromodomain-containing protein is BRDT. In certain embodiments, the gene regulated by the bromodomain-containing protein is BRDT(1). In certain embodiments, the gene regulated by the bromodomain-containing protein is BRDT(2). In certain embodiments, the gene regulated by a bromodomain-containing protein is a gene regulated by TBP (TATA box binding protein)-associated factor protein (TAF). In certain embodiments, the gene regulated by the bromodomain-containing protein is TAF1. In certain embodiments, the gene regulated by the bromodomain-containing protein is TAF1L. In certain embodiments, the gene regulated by a bromodomain-containing protein is a gene regulated by CREB binding protein (CBP). In certain embodiments, the gene regulated by the bromodomain-containing protein is a gene regulated by the E1A binding protein p300 (EP300).

The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such methods of preparation include bringing into association a compound described herein (i.e., the "active ingredient") with the carrier or excipient, and/or one or more other accessory ingredients, and then optionally and/or, if desired, forming and/or packaging the product into desired single or multiple dose units.

Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk quantities as a single unit dose and/or as a plurality of single unit doses. A "unit dose" is a discrete amount of a pharmaceutical composition containing a predetermined amount of active ingredient. The amount of active ingredient will generally be equal to the dosage of active ingredient that will be administered to the subject and/or will be one-half or one-third of such dosage. It is a convenient fraction.

The relative amounts of active ingredients, pharmaceutically acceptable excipients, and/or any additional ingredients in the pharmaceutical compositions described herein will depend on the identity, size, and/or condition of the subject being treated. Variations will vary accordingly, and also depending on the route by which the composition is to be administered. The composition may contain between 0.1% and 100% (w/w) of active ingredient.

Pharmaceutically acceptable excipients used in the manufacture of the provided pharmaceutical compositions include inert diluents, dispersants and/or granulating agents, surfactants and/or emulsifiers, disintegrants, binders. agents, preservatives, buffers, lubricants, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coatings, sweetening agents, flavoring agents, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, Includes sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

Exemplary granulating and/or dispersing agents are potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponges, cation exchange resins. , calcium carbonate, silicate, sodium carbonate, crosslinked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, crosslinked sodium carboxymethylcellulose (croscarmellose), methylcellulose, alpha starch (Starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

Exemplary surfactants and/or emulsifiers include natural emulsifiers such as acacia, agar, alginic acid, sodium alginate, tragacanth, chondrix, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, Cholesterol, waxes, and lecithin), colloidal clays (for example, bentonite (aluminum silicate) and Veegum (aluminum magnesium silicate)), long chain amino acid derivatives, high molecular weight alcohols (for example, stearyl alcohol, cetyl alcohol, oleyl alcohol) , triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (for example, carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers) , carrageenan, cellulose derivatives (for example, sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (for example, polyoxyethylene sorbitan monolaurate (Tween® ) 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80)), polyoxyethylene esters (e.g. Ethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters ( Examples include Cremophor®), polyoxyethylene ethers (e.g. polyoxyethylene lauryl ether (Brij® 30)), poly(vinylpyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, Sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, Poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride , docusate sodium, and/or mixtures thereof.

Exemplary binders are starches (for example, cornstarch and starch paste), gelatin, sugars (for example, sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic rubbers (for example, Acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of plantain extract (isapol husk), carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose , microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum®, and deciduous pine arabogalactan), alginate, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, poly Including methacrylates, waxes, water, alcohols, and/or mixtures thereof.

Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoal preservatives, alcoholic preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

Exemplary antioxidants are alpha-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite. , sodium metabisulfite, and sodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (eg, sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.); Citric acid and its salts and hydrates (e.g. citric acid monohydrate), fumaric acid and its salts and hydrates, malate and its salts and hydrates, phosphoric acid and its salts and hydrates , and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidourea, Includes phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

Exemplary alcoholic preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopheryl acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate. (SLES), Sodium Bisulfite, Sodium Metabisulfite, Potassium Sulfite, Potassium Metabisulfite, Glydant® Plus, Phenonip®, Methylparaben, Germall® 115, Germaben® II, Includes Neolone®, Kathon®, and Euxyl®.

Exemplary buffers include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium gluvionate, calcium glucept, calcium gluconate, D-gluconate, Calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, Dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, Includes sodium phosphate mixture, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, lauryl including sodium sulfate, and mixtures thereof.

Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cadet, chamomile, canola, caraway, carnauba, castor oil, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, Cottonseed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, loofah, grape seeds, hazelnuts, hyssop, isopropyl myristate, jojoba, kukui nuts, lavandin, lavender, lemon, litse cubeba, macadamia nuts, mallow, mango seeds, meadowfoam seeds , mink, nutmeg, olive, orange, orange roughy, palm, oil palm seeds, peach kernels, peanuts, poppy seeds, pumpkin seeds, rapeseed, rice bran, rosemary, safflower, sandalwood, sasanquat, savory, seaweed, sesame, Includes shea butter, silicone, soybean, sunflower, tea tree, thistle, camellia, vetiver, walnut, and wheat germ. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyl dodecanol, oleyl alcohol, silicone oil. , and mixtures thereof.

Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, liquid dosage forms contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers (ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate). , benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, etc.), oils (such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, It may also include fatty acid esters of tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are prepared using solubilizing agents such as Cremophor®, alcohols, oils, denatured oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof. mixed with the agent.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation is a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. obtain. Acceptable vehicles and solvents that may be employed include water, Ringer's solution, U.S. S. P. , and isotonic sodium chloride solutions. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

Injectable formulations may incorporate sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use, for example by filtration through a bacteria-retaining filter. It can be sterilized by this.

In order to prolong the effects of a drug, it is often desirable to delay absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by the use of liquid suspensions of poorly water-soluble, crystalline or amorphous materials. The rate of absorption of a drug then depends on its rate of dissolution, which, in turn, may depend on crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered drug forms may be accomplished by dissolving or suspending the drug in an oil vehicle.

Compositions for rectal or vaginal administration are typically prepared by mixing the conjugates described herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, etc. Suppositories, or suppository waxes, which may be prepared are solid at ambient temperature but liquid at body temperature, thus melting in the rectal or vaginal cavity to release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is combined with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and/or (a) a filler or Bulking agents (such as starch, lactose, sucrose, glucose, mannitol, and silicic acid), (b) binders (such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia), (c) humectants ( (e) solution retarding agents (such as paraffin); (f) absorption enhancers (such as quaternary ammonium compounds), (g) wetting agents (such as cetyl alcohol and glycerol monostearate), (h) absorbents (such as kaolin and bentonite clay), and (i) lubricants ( talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc.), and mixtures thereof. For capsules, tablets, and pills, the dosage form may include a buffering agent.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmacological art. They may optionally contain opacifying agents and are compositions in which they release only, or preferentially, the active ingredient(s) in certain parts of the intestinal tract in an optionally delayed manner. It can be of. Examples of encapsulating compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may be employed as fillers in soft- and hard-filled gelatin capsules using such excipients as lactose or milk sugar and high molecular weight polyethylene glycols and the like.

The active ingredient may be in microencapsulated form with one or more excipients as indicated above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings, and other coatings well known in the pharmaceutical formulation art. . In such solid dosage forms, the active ingredient may be mixed with at least one inert diluent such as sucrose, lactose, or starch. Such solid dosage forms may contain, in accordance with conventional practice, additional substances other than inert diluents, such as tabletting lubricants and other tabletting aids, such as, for example, magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also include a buffering agent. They may optionally contain opacifying agents and they are compositions that release only, or preferentially, the active ingredient(s) in certain parts of the intestinal tract in any delayed manner. It can be a thing. Examples of encapsulating agents that can be used include polymeric substances and waxes.

Dosage forms for topical and/or transdermal administration of the compounds described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / Or a patch may be included. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any necessary preservatives and/or buffers as may be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of active ingredients to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or in addition, the rate may be controlled either by providing a rate controlling membrane and/or by dispersing the active ingredient in a polymeric matrix and/or gel.

Intradermal compositions may be administered by a device that limits the effective penetration length of the needle into the skin. Alternatively or in addition, conventional syringes can also be used for the classic Mantoux method of intradermal administration. Jet injection devices are preferred that deliver liquid formulations to the dermis via a liquid jet syringe and/or via a needle that produces a jet that penetrates the stratum corneum and reaches the dermis. Ballistic powder/particle delivery devices that use compressed gas to accelerate the compound in powder form through the outer layers of the skin into the dermis are preferred.

Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid formulations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or Pastes and/or solutions and/or suspensions are included. Topically administrable formulations may contain, for example, from about 1% to about 10% (w/w) of active ingredient, but the concentration of active ingredient can be comparable to the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further include one or more additional ingredients described herein.

The pharmaceutical compositions described herein can be prepared, packaged, and/or sold in formulations suitable for oral or pulmonary administration. Such formulations may include dry particles containing the active ingredient and having a diameter ranging from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of a dry powder for administration, said administration using a device comprising a dry powder reservoir into which a stream of propellant is directed to disperse the powder; and/or using a self-propelled solvent/powder dispensing container, such as a device containing the active ingredient dissolved and/or suspended in a low-boiling propellant in a closed container. Such a powder comprises particles, wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. . Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include solid fine powder diluents such as sugars and are conveniently presented in unit dosage form.

Low boiling propellants generally include liquid propellants that have a boiling point below 65° F. at atmospheric pressure. Generally, the propellant may constitute 50-99.9% (w/w) of the composition and the active ingredient may constitute 0.1-20% (w/w) of the composition. . Propellants may further include liquid non-ionic and/or solid anionic surfactants, and/or solid diluents, which may have a particle size similar to the particles containing the active ingredient. Additional ingredients may also be included.

Pharmaceutical compositions described herein that are formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations may be prepared, packaged, and/or sold as optionally sterile, aqueous and/or dilute alcoholic solutions and/or suspensions containing the active ingredient, conveniently in the presence of any nebulizer. and/or may be administered using a micronization device. Such formulations may further contain one or more additional ingredients including, but not limited to, flavoring agents such as sodium saccharin, volatile oils, buffers, surfactants, and/or preservatives such as methyl hydroxybenzoate. But that's fine. Droplets provided by this route of administration may have an average diameter ranging from about 0.1 to about 200 nanometers.

Formulations described herein as useful for pulmonary delivery are useful for intranasal delivery of the pharmaceutical compositions described herein. Another formulation suitable for intranasal administration is a coarse powder containing the active ingredient and having an average particle size of about 0.2 to 500 micrometers. Such formulations are administered by rapid inhalation through the nasal cavity from a container of powder held near the nostrils.

Formulations for nasal administration may contain as much of the active ingredient as, for example, as little as about 0.1% (w/w) to 100% (w/w), including one or more of the active ingredients described herein. Additional ingredients may also be included. The pharmaceutical compositions described herein can be prepared, packaged, and/or sold as a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods and may contain, for example, 0.1-20% (w/w) of the active ingredient. , the remainder comprising an orally soluble and/or degradable composition and, optionally, one or more additional ingredients as described herein. Alternatively, formulations for buccal administration may include powders and/or aerosolized and/or micronized solutions and/or suspensions containing the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have average particle and/or droplet sizes ranging from about 0.1 to about 200 nanometers; It may also contain one or more additional ingredients as described herein.

The pharmaceutical compositions described herein can be prepared, packaged, and/or sold as a formulation for ophthalmic administration. Such formulations include, for example, 0.1% (w/w) to 0.1/1.0% (w/w) solutions of the active ingredient in an aqueous or oily liquid carrier or excipient and/or It may also be in the form of eye drops, including suspensions. Such drops may further include buffers, salts, and/or one or more other additional ingredients described herein. Other ophthalmically administrable formulations that are useful include those containing the active ingredients in microcrystalline form and/or in liposomal formulations. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.

Although the description of pharmaceutical compositions provided herein is directed primarily to pharmaceutical compositions suitable for administration to humans, it is understood that such compositions are generally suitable for administration to animals of all kinds. will be understood by those skilled in the art. The modification of pharmaceutical compositions suitable for human administration to render them suitable for administration to a variety of animals is well understood, and those skilled in the art of veterinary pharmacology will recognize that such modifications It may be designed and/or implemented using experimental methods.

The compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The particular therapeutically effective dose level for any particular subject or organism will depend on the severity of the disease and disorder being treated; the activity of the particular active ingredient employed; the particular composition employed; age, weight, general health, sex, and diet; time of administration, route of administration, and rate of excretion of the specific active ingredient employed; duration of treatment; in combination with the specific active ingredient employed; It will depend on a variety of factors, including or the drugs used concurrently; and similar factors well known in the medical art.

The compounds and compositions provided herein can be administered enterally (eg, orally), parenterally, intravenously, intramuscularly, intraarterially, intramedullary, intrathecally, subcutaneously, intracerebroventricularly, transdermally, subcutaneously. By any route, including internally, rectally, intravaginally, intraperitoneally, topically (e.g., by powder, ointment, cream, and/or drops), mucosally, nasally, orally, sublingually; It may be administered by intraluminal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (eg, systemic intravenous injection), local administration via the blood and/or lymphatic supply, and/or direct administration to the affected area. Generally, the most appropriate route of administration will depend on the nature of the drug (e.g., its stability in the environment of the gastrointestinal tract) and/or the condition of the subject (e.g., whether the subject can tolerate oral administration). It will depend on various factors involved. In certain embodiments, the compounds or pharmaceutical compositions described herein are suitable for topical administration to the eye of a subject.

The precise amount of compound required to achieve an effective amount will depend, for example, on the species, age, and general condition of the subject, the severity of the side effect or disorder, the identity of the particular compound, the mode of administration, etc. Therefore, it will vary depending on the subject. The desired dosage can be delivered three times a day, twice a day, once a day, every other day, every second day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage is administered in multiple doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more doses). can be delivered using An effective amount may be encompassed in a single dose (eg, a single oral dose) or multiple doses (eg, multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to tissue or cells, any two doses of the multiple doses are different amounts or substantially the same amount of the present invention. This includes the compounds described in . In certain embodiments, when multiple doses are administered to a subject or applied to tissues or cells, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissues or cells is within a day. 3 doses per day, 2 doses per day, 1 dose per day, 1 dose every other day, 1 dose every 3 days, 1 dose every week, 1 dose every 2 weeks, 1 dose every 3 weeks, or every 4 weeks. 1 dose. In certain embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is one dose per day. In certain embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is two doses per day. In certain embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is 3 doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to tissue or cells, the time period between the first and last dose of the multiple doses is 1 day, 2 days, 4 days. , 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7 years , 10 years, 15 years, 20 years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the period between the first and last dose of the multiple doses is 3 months, 6 months, or 1 year. In certain embodiments, the period of time between the first and last dose of the multiple doses is the period of life of the subject, tissue, or cell. In certain embodiments, the doses described herein (eg, either a single dose or multiple doses) are independently 0.1 μg and 1 μg of a compound described herein. between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g (inclusive). In certain embodiments, doses described herein independently include between 1 and 3 mg, inclusive, of a compound described herein. In certain embodiments, doses described herein independently include between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, doses described herein independently include between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, doses described herein independently include between 30 mg and 100 mg, inclusive, of a compound described herein.

In certain embodiments, an effective amount of the compound for one or more administrations per day to a 70 kg adult includes about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or It may contain from about 100 mg to about 1000 mg.

In certain embodiments, the compounds described herein are administered at dosage levels of about 100% of a subject's body weight per day one or more times per day to obtain the desired therapeutic and/or prophylactic effect. from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about sufficient to deliver up to 30 mg/kg, from about 0.01 mg/kg to 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, more preferably from about 1 mg/kg to about 25 mg/kg. obtain.

It will be appreciated that the dosage ranges as described herein provide guidance for the administration of the provided pharmaceutical compositions to adults. For example, the amount administered to a child or adolescent can be determined by a physician or person skilled in the art, and may be less than or the same as the amount administered to an adult.

It will also be appreciated that the compounds or compositions described herein can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). Dew. The compounds or compositions may be administered in combination with additional pharmaceutical agents, which further enhance their activity (e.g., treatment of a disease in a subject in need thereof, prophylaxis of a disease). to reduce the risk of developing a disease in a subject who needs it, to inhibit the replication of a virus, to kill a virus, to reduce the risk of developing a disease in a subject who needs it, to inhibit the replication of a virus, to kill a virus, to reduce the risk of developing a disease inhibiting the activity of a domain-containing protein, inhibiting the activity of a bromodomain in a subject or cell, acetyl-lysine of a second protein (e.g., a histone) of a bromodomain of a bromodomain-containing protein in a subject or cell; modulating (e.g., inhibiting) transcriptional elongation; modulating (e.g., transcription) expression (e.g., transcription) of genes regulated by bromodomain-containing proteins in a subject or cell; activity (e.g., potency and/or effectiveness) in inhibiting), inducing apoptosis in a cell, inducing apoptosis in a subject, inducing G1 phase arrest in a subject or a cell; improve bioavailability, and/or safety, reduce drug resistance, reduce and/or modify their metabolism, inhibit their excretion, and/or in the body of a subject. alter their distribution of. It will also be appreciated that the treatment employed may achieve a desired effect on the same disorder and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein that includes a compound described herein and an additional pharmaceutical agent is a pharmaceutical composition that includes one, but not both, the compound and the additional pharmaceutical agent. shows a synergistic effect that does not exist in

A compound or composition may be administered simultaneously with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as a combination therapy, for example. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include drug compounds (e.g., compounds as provided in the Code of Federal Regulations (CFR) approved by the U.S. Food and Drug Administration for human or veterinary use), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, anti- Includes small organic molecules such as sense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease described herein. Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. Additional pharmaceutical agents may also be administered in a single dose or separately in different doses with each other and/or with the compounds or compositions described herein. The particular combination to be employed in a regimen depends on the compatibility of the compounds described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. The effects of this will be taken into consideration. Generally, it is expected that the additional pharmaceutical agent(s) utilized in combination will be utilized at levels not exceeding those at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

Additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenic agents, anti-inflammatory agents, immunosuppressive agents, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents. , anti-diabetic agents, anti-allergic agents, contraceptives, and analgesics. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an antileukemic agent. In certain embodiments, the additional agent is ABITREXATE, ADE, Adriamycin RDF, Ambochlorin, ARRANON, ARZERRA, BOSULIF, BUSULFEX, CAMPATH ( alemtuzumab), CERUBIDINE (daunorubicin hydrochloride), CLAFEN (cyclophosphamide), CLOFAREX (clofarabine), CLOLAR (clofarabine), CVP, CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), ERWINAZE (asparaginase from Erwinia Chrysanthemi) ), FLUDARA (fludarabine phosphate), FOLEX (methotrexate), FOLEX PFS (methotrexate), GAZYVA (obinutuzumab), GLEEVEC (imatinib mesylate), Hyper-CVAD, ICLUSIG (ponatinib hydrochloride), IMBRUVICA (ibrutinib), LEUKERAN (chlorambucil) ), LINFOLIZIN (chlorambucil), MARQIBO (vincristine sulfate liposomes), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), mitoxantrone hydrochloride, MUSTARGEN (mechlorethamine hydrochloride), MYLERAN (busulfan), NEOSAR ( cyclophosphamide), ONCASPAR (peguasparagase), PURINETHOL (mercaptopurine), PURIXAN (mercaptopurine), rubidomycin (daunorubicin hydrochloride), SPRYCEL (dasatinib), SYNRIBO (omacetaxine mepesuccinate), TARABINE PFS (cytarabine), TASIGNA (nilotinib), TREANDA (bendamustine hydrochloride), TRISENOX (arsenic trioxide), VINCASAR PFS (vincristine sulfate), ZYDELIG (idelalisib), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is an anti-lymphoma agent. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABVD, ABVE, ABVE-PC, ADCETRIS (brentuximab vedotin), Adriamycin PFS (doxorubicin hydrochloride), Adriamycin RDF (doxorubicin hydrochloride), AMBOCHLORIN (chlorambucil) , AMBOCLORIN (chlorambucil), ARRANON (nelarabine), BEACOPP, BECENUM (carmustine), BELEODAQ (belinostat), BEXXAR (tositumomab and iodine I131 tositumomab), BICNU (carmustine), BLENOXANE (bleomycin), CARMUBRIS (carmustine), CHOP, CLAFEN (cyclophosphamide), COPP, COPP-ABV, CVP, CYTOXAN (cyclophosphamide), DEPOCYT (liposomal cytarabine), DTIC-DOME (dacarbazine), EPOCH, FOLEX (methotrexate), FOLEX PFS (methotrexate) , FOLOTYN (pralatrexate), HYPER-CVAD, ICE, IMBRUVICA (ibrutinib), INTRON A (recombinant interferon alpha-2b), ISTODAX (romidepsin), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), lomustine, MATULANE (procarbazine hydrochloride) ), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), MOPP, MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), NEOSAR (cyclophosphamide), OEPA, ONTAK (denileukine diftitox) ), OPPA, R-CHOP, REVLIMID (lenalidomide), RITUXAN (rituximab), STANFORD V, TREANDA (bendamustine hydrochloride), VAMP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VINCASAR PFS (sulfate) vincristine), ZEVALIN (ibritumomab tiuxetan), ZOLINZA (vorinostat), ZYDELIG (idelalisib), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is REVLIMID, DACOGEN, VIDAZA, CYTOSAR-U, IDAMYCIN, CERUBIDINE, LEUKERAN, NEOSAR phosphamide), FLUDARA (fludarabine), LEUSTATIN (cladribine), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is ABITREXATE (methotrexate), ABRAXANE (paclitaxel albumin stabilized nanoparticle formulation), AC, AC-T, ADE, Adriamycin PFS (doxorubicin hydrochloride), ADRUCIL (fluorouracil), AFINITOR (everolimus). ), AFINITORDISPERZ (everolimus), ALDARA (imiquimod), ALIMTA (pemetrexed disodium), AREDIA (pamidronate disodium), ARIMIDEX (anastrozole), AROMASIN (exemestane), AVASTIN (bevacizumab), BECENUM (carmustine), BEP , BICNU (carmustine), BLENOXANE (bleomycin), CAF, CAMPTOSAR (irinotecan hydrochloride), CAPOX, CAPRELSA (vandetanib), CARBOPLATIN-TAXOL, CARMUBRIS (carmustine), CASODEX (bicalutamide), CEENU (lomustine), CERUBIDINE (daunorubicin hydrochloride) , CERVARIX (recombinant HPV bivalent vaccine), CLAFEN (cyclophosphamide), CMF, COMETRIQ (cabozantinib-s-malate), COSMEGEN (dactinomycin), CYFOS (ifosfamide), CYRAMZA (ramucirumab), CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), DACOGEN (decitabine), DEGARELIX, DOXIL (doxorubicin hydrochloride liposome), doxorubicin hydrochloride, DOX-SL (doxorubicin hydrochloride liposome), DTIC-DOME (dacarbazine), EFUDEX (fluorouracil), ELLENCE (epirubicin hydrochloride), ELOXATIN (oxaliplatin), ERBITUX (cetuximab), ERIVEDGE (vismodegib), ETOPOPHOS (etoposide phosphate), EVACET (doxorubicin hydrochloride liposome), FARESTON (toremifene), FASLODEX (fulvestrant), FEC, FEMARA (letrozole), FLUOROPLEX (fluorouracil), FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV, GARDASIL (recombinant human papillomavirus (HPV) tetravalent vaccines), GEMCITABINE-CISPLATIN, GEMCITABINE-OXALIPLATIN, GEMZAR (gemcitabine hydrochloride), GILOTRIF (afatinib dimaleate), GLEEVEC (imatinib mesylate), GLIADEL (carmustine implant), GLIADEL WAFER (carmustine implant), HERCEPTIN (trastuzumab) ), HYCAMTIN (topotecan hydrochloride), IFEX (ifosfamide), IFOSFAMIDUM (ifosfamide), INLYTA (axitinib), INTRON A (recombinant interferon alpha-2b), IRESSA (gefitinib), IXEMPRA (ixabepilone), JAKAFI (ruxolitinib phosphate), JEVTANA (cabazitaxel), KADCYLA (ado-trastuzumab emtansine), KEYTRUDA (pembrolizumab), KYPROLIS (carfilzomib), LIPODOX (doxorubicin hydrochloride liposomes), LUPRON (leuprolide acetate), LUPRON DEPOT (leuprolide acetate), LUPRON DEPOT-3 MONTH ( LUPRON DEPOT-4 MONTH (leuprolide acetate), LUPRON DEPOT-PED (leuprolide acetate), MEGACE (megestrol acetate), MEKINIST (trametinib), METHAZOLASTONE (temozolomide), METHOTREXATE LPF (methotrexate), MEXATE (methotrexate) ), MEXATE-AQ (methotrexate), mitoxantrone hydrochloride, MITOZYTREX (mitomycin c), MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine hydrochloride), MUTAMYCIN (mitomycin c), MYLOSAR (azacytidine), NAVELBINE (vinorelbine tartrate), NEOSAR ( cyclophosphamide), NEXAVAR (sorafenib tosylate), NOLVADEX (tamoxifen citrate), NOVALDEX (tamoxifen citrate), OFF, PAD, PARAPLAT (carboplatin), PARAPLATIN (carboplatin), PEG-INTRON (pegylated interferon alpha-2b) ), PEMETREXED DISODIUM, PERJETA, PLATINOL, PLATINOL-AQ, POMALYST, prednisone, PROLEUKIN, PROLIA, PROVENGE, REVLIMID , rubidomycin (daunorubicin hydrochloride), SPRYCEL (dasatinib), STIVARGA (regorafenib), SUTENT (sunitinib malate), SYLATRON (peginterferon alfa-2b), SYLVANT (siltuximab), SYNOVIR (thalidomide), TAC, TAFINLAR (dabrafenib), TARABINE PFS (cytarabine), TARCEVA (erlotinib hydrochloride), TASIGNA (nilotinib), TAXOL (paclitaxel), TAXOTERE (docetaxel), TEMODAR (temozolomide), THALOMID (thalidomide), TOPOSAR (etoposide), TORISEL (temsirolimus), TPF, TRISENOX (arsenic trioxide), TYKERB (lapatinib tosylate), VECTIBIX (panitumumab), VEIP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine sulfate), VEPESID (etoposide), VIADUR (leuprolide acetate), VIDAZA ( azacitidine), VINCASAR PFS (vincristine sulfate), VOTRIENT (pazopanib hydrochloride), WELLCOVORIN (leucovorin calcium), XALKORI (crizotinib), XELODA (capecitabine), XELOX, XGEVA (denosumab), XOFIGO (radium-223 chloride), XTANDI (enzalutamide) , YERVOY (ipilimumab), ZALTRAP (ziv-aflibercept), ZELBORAF (vemurafenib), ZOLADEX (goserelin acetate), ZOMETA (zoledronic acid), ZYKADIA (ceritinib), ZYTIGA (abiraterone acetate), or a combination thereof. In certain embodiments, the additional pharmaceutical agent is an antiviral agent. In certain embodiments, the additional agent is a bromodomain-containing protein binder. In certain embodiments, the additional agent is a bromodomain binder. In certain embodiments, the additional agent is a binder or inhibitor of bromodomain-containing proteins. In certain embodiments, the additional agent is a bromodomain binder or inhibitor. In certain embodiments, the additional agent is an epigenetic modulator or transcriptional modulator (e.g., a DNA methyltransferase inhibitor, a histone deacetylase inhibitor (HDAC inhibitor), a lysine methyltransferase inhibitor), an antimitotic agent (e.g., a taxane). and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors) , Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, and other agents that promote differentiation. In certain embodiments, the compounds or pharmaceutical compositions described herein are used to treat anti-inflammatory agents including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, viral agents. may be administered in combination with cancer therapy. In certain embodiments, the additional pharmaceutical agent is a bromodomain-containing protein binder. In certain embodiments, the additional pharmaceutical agent is a bromodomain binder. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of bromodomain-containing proteins. In certain embodiments, the additional pharmaceutical agent is a bromodomain binder or inhibitor. In certain embodiments, the additional pharmaceutical agent is a pigenetic modulator or transcriptional modulator (e.g., a DNA methyltransferase inhibitor, a histone deacetylase inhibitor (HDAC inhibitor), a lysine methyltransferase inhibitor), an antimitotic agent (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors). ), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acid, and other agents that promote differentiation. In certain embodiments, the compounds or pharmaceutical compositions described herein may be administered in combination with anti-cancer agents including, but not limited to, surgery, radiation therapy, and chemotherapy.
In certain embodiments, the additional pharmaceutical agent is an immune modulator (eg, a checkpoint inhibitor). In some embodiments, the immune modulator activates the expression or activity of a stimulatory immune molecule. In some embodiments, the stimulatory immune molecule is selected from the group consisting of 4-1BB (CD137), CD137L, OX40, OX40L, ICOS, CD40, CD40L, CD70, CD27, CD28, CD80, CD86, B7RP1, and HVEM. be done. In some embodiments, immune modulators inhibit the expression or activity of inhibitory immune molecules (eg, immune checkpoint molecules). In some embodiments, the immune modulator is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is from the group consisting of CTLA-4, PD-1, PDL-1, PDL-2, TIM3, LAG3, B7-H3, B7-H4, BTLA, GAL9, and A2aR. This is an interview about immune checkpoint proteins to choose from. In some embodiments, the immune modulator is a peptide, antibody, interfering RNA, or small molecule. In some embodiments, the immune modulator is a monoclonal antibody or an Ig fusion protein. In some embodiments, the immune modulator is a stimulatory immune molecule (e.g., 4-1BB (CD137), CD137L, OX40, OX40L, ICOS, CD40, CD40L, CD70, CD27, CD28, CD80, CD86, B7RP1, or It is an agonistic antibody directed against HVEM. In some embodiments, the immune modulator is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is a peptide, antibody, interfering RNA, or small molecule. In some embodiments, the immune checkpoint inhibitor is a monoclonal antibody or an Ig fusion protein. In some embodiments, the immune checkpoint inhibitor is from the group consisting of CTLA-4, PD-1, PDL-1, PDL-2, TIM3, LAG3, B7-H3, B7-H4, BTLA, GAL9, and A2aR. Inhibitors of selected immune checkpoint proteins.

Also covered by this disclosure are kits (eg, pharmaceutical packs). Kits provided may include a pharmaceutical composition or compound described herein and a container (eg, a vial, ampoule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, the provided kits optionally further include a second container containing a pharmaceutical excipient for diluting or suspending a pharmaceutical composition or compound described herein. good. In some embodiments, the pharmaceutical compositions or compounds described herein provided in a first container and a second container are combined to form a unit dosage form.

Thus, in one aspect, provided are compounds described herein, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, sterics thereof. A kit comprising a first container containing an isomer, isotopically labeled derivative, or prodrug, or a pharmaceutical composition thereof. In certain embodiments, the kits are useful for treating and/or preventing the diseases described herein in a subject in need thereof. In certain embodiments, the kits are useful for treating the diseases described herein in a subject in need thereof. In certain embodiments, the kits are useful for preventing the diseases described herein in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease described herein in a subject in need thereof. In certain embodiments, the kit is useful for male contraception. In certain embodiments, the kits are useful for inhibiting spermatogenesis. In certain embodiments, the kits are useful for inhibiting viral replication. In certain embodiments, the kits are useful for killing viruses. In certain embodiments, the kits are useful for inhibiting the activity (eg, aberrant activity, such as increased activity) of a bromodomain-containing protein in a subject or cell. In certain embodiments, the kits are useful for inhibiting bromodomain activity (eg, abnormal activity, such as increased activity) in a subject or cell. In certain embodiments, the kit is useful for inhibiting the binding of a bromodomain of a bromodomain-containing protein to an acetyl-lysine residue of a second protein (eg, a histone) in a subject or cell. In certain embodiments, the kits are useful for modulating (eg, inhibiting) transcriptional elongation in a subject or cell. In certain embodiments, the kits are useful for modulating (eg, downregulating or inhibiting) the expression (eg, transcription) of a gene regulated by a bromodomain-containing protein in a subject or cell. In certain embodiments, the kits are useful for inducing apoptosis in cells. In certain embodiments, the kit is useful for inducing apoptosis in a subject. In certain embodiments, the effective amount is useful for inducing G1 phase arrest in a subject or cell.

In certain embodiments, the kits are useful for screening libraries of compounds to identify compounds useful in the methods of the present disclosure.

In certain embodiments, the kits described herein further include instructions for using the kit in the methods of the present disclosure (e.g., instructions for administering a compound or pharmaceutical composition described herein to a subject). Includes instructions for using the kit, such as. The kits described herein may also include information as required by regulatory agencies such as the US Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescribing information. In certain embodiments, the kits and instructions provide for treatment and/or prevention of the diseases described herein in a subject in need thereof. In certain embodiments, the kits and instructions provide for treatment of the diseases described herein in a subject in need thereof. In certain embodiments, the kits and instructions provide for the prevention of the diseases described herein in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease described herein in a subject in need thereof. In certain embodiments, the kit and instructions provide male contraception. In certain embodiments, the kit and instructions provide for inhibiting viral replication. In certain embodiments, the kit and instructions provide for killing viruses. In certain embodiments, the kits and instructions provide for inhibiting the activity (eg, aberrant activity, such as increased activity) of a bromodomain-containing protein in a subject or cell. In certain embodiments, the kits and instructions provide for inhibiting activity (eg, abnormal activity, such as increased activity) of a bromodomain in a subject or cell. In certain embodiments, the kit and instructions provide for inhibiting binding of a bromodomain of a bromodomain-containing protein to an acetyl-lysine residue of a second protein (eg, a histone) in a subject or cell. In certain embodiments, the kits and instructions provide for modulating (eg, inhibiting) transcription elongation. In certain embodiments, the kits and instructions provide for modulating (eg, downregulating or inhibiting) the expression (eg, transcription) of a gene regulated by a bromodomain-containing protein in a subject or cell. In certain embodiments, the kit and instructions provide for inducing apoptosis of cells in vitro. In certain embodiments, the kit and instructions provide for inducing apoptosis of cells in a subject. In certain embodiments, the kit and instructions provide for inducing G1 phase arrest in a subject or cell. In certain embodiments, the kits and instructions provide for screening libraries of compounds to identify compounds that are useful in the methods of the present disclosure. The kits described herein may include one or more additional pharmaceutical agents described herein as separate compositions.

Methods of Treatment and Uses Compounds described herein (for example, compounds of formulas (I), (II), (III), (IV), (V), and (VI)) may be It was found to bind to domain-containing proteins. In certain embodiments, the compounds described herein bind to bromodomain-containing proteins. Without wishing to be bound by any particular theory, it is believed that the compounds described herein bind within the bromodomain pocket of bromodomain-containing proteins. In certain embodiments, the compounds described herein bind simultaneously in two different bromodomain pockets of a bromodomain-containing protein. In certain embodiments, the compounds described herein bind within the binding pocket of a bromodomain by mimicking an acetyl-lysine residue of a second protein (eg, a histone).

In certain embodiments, the compounds described herein non-covalently bind to bromodomain-containing proteins. In certain embodiments, the compounds described herein reversibly bind bromodomain-containing proteins. In certain embodiments, compounds described herein inhibit the activity (eg, abnormal activity, increased activity) of bromodomain-containing proteins. In certain embodiments, compounds described herein inhibit bromodomain activity (eg, abnormal activity, increased activity). In certain embodiments, the activity of the bromodomain is determined by the activity of an acetylated lysine residue (e.g., an acetylated lysine residue on the N-terminal tail of a histone) that may be part of another protein or peptide (e.g., a histone). ) is the ability of bromodomains to bind to In certain embodiments, the compounds described herein specifically bind to a bromodomain-containing protein (e.g., to a bromodomain-containing protein, rather than to a different bromodomain-containing protein, and/or to a bromodomain-containing protein). binds with higher binding affinity than for non-proteins). In certain embodiments, the compounds described herein specifically bind to bromodomains of bromodomain-containing proteins (e.g., to bromodomains of bromodomain-containing proteins versus non-bromodomains of bromodomain-containing proteins). binds with higher binding affinity than that for In certain embodiments, a compound described herein non-specifically binds to a bromodomain-containing protein (eg, binds to a bromodomain of a bromodomain-containing protein). In certain embodiments, the compounds described herein reduce transcriptional elongation. In certain embodiments, the compounds described herein disrupt the subcellular localization of bromodomain-containing proteins. In certain embodiments, the compounds described herein reduce chromatin binding. In certain embodiments, the compounds described herein inhibit chromatin formation by reducing the binding of proteins (eg, histones) to DNA. In certain embodiments, the compounds described herein inhibit the binding of histone H4 Kac peptide to the bromodomain of a bromodomain-containing protein. In certain embodiments, the compounds described herein form one or more hydrogen bonds with an evolutionarily conserved asparagine in the bromodomain of a bromodomain-containing protein. In certain embodiments, the asparagine is Asn140 of BRD4 (1) and Asn429 of BRD2 (2). In certain embodiments, the bromodomain-containing protein is BRD4 or BRD2; and the asparagine is Asn140 of BRD4 (1) and Asn429 of BRD2 (2). In certain embodiments, the compounds described herein compete with chromatin to bind to bromodomains in the cellular environment. It is therefore anticipated that the compounds described herein may be useful in treating diseases associated with the activity of bromodomain-containing proteins, such as proliferative diseases.

As described herein, the compounds of the invention are bivalent and therefore capable of binding to two different sites on a single protein simultaneously. In certain embodiments, the compounds described herein bind to two different sites on a bromodomain-containing protein simultaneously. In certain embodiments, compounds of the invention bind simultaneously to bromodomain 1 (BD1) and bromodomain 2 (BD2) of bromodomain-containing proteins. In certain embodiments, compounds provided herein bind simultaneously to two different bromodomains of bromodomain-containing protein 4 (BRD4). In certain embodiments, compounds provided herein bind simultaneously to BD1 and BD2 of BRD4.

The compounds described herein may bind to or inhibit the activity of bromodomain-containing proteins. In certain embodiments, the bromodomain-containing protein is a bromo and specific end (BET) protein. In certain embodiments, the bromodomain-containing protein is BRD2. In certain embodiments, the bromodomain-containing protein is BRD2(1). In certain embodiments, the bromodomain-containing protein is BRD2 (2). In certain embodiments, the bromodomain-containing protein is BRD3. In certain embodiments, the bromodomain-containing protein is BRD3(1). In certain embodiments, the bromodomain-containing protein is BRD3(2). In certain embodiments, the bromodomain-containing protein is BRD4. In certain embodiments, the bromodomain-containing protein is BRD4(1). In certain embodiments, the bromodomain-containing protein is BRD4(2). In certain embodiments, the bromodomain-containing protein is BRDT. In certain embodiments, the bromodomain-containing protein is BRDT(1). In certain embodiments, the bromodomain-containing protein is BRDT(2). In certain embodiments, the bromodomain-containing protein is TBP (TATA box binding protein)-associated factor protein (TAF). In certain embodiments, the bromodomain-containing protein is TAF1. In certain embodiments, the bromodomain-containing protein is TAF1L. In certain embodiments, the bromodomain-containing protein is CREB binding protein (CBP). In certain embodiments, the bromodomain-containing protein is E1A binding protein p300 (EP300).

The binding affinity of the compounds described herein for bromodomain-containing proteins is determined using methods known in the art, e.g., isothermal titration calorimetry (ITC). may be measured by the dissociation constant (K _d ) value of an adduct between the compound and the bromodomain-containing protein. In certain embodiments, the adduct comprises a compound described herein and a bromodomain-containing protein bound to each other (eg, covalently or non-covalently). In certain embodiments, the K _d value of the adduct is at most about 100 μM, at most about 30 μM, at most about 10 μM, at most about 3 μM, at most about 1 μM, at most about 300 nM, at most about 100 nM, at most about 30 nM, up to about 10 nM, up to about 3 nM, or up to about 1 nM. In certain embodiments, the K _d value of the adduct is at least about 1 nM, at least about 10 nM, at least about 100 nM, at least about 1 μM, at least about 10 μM, or at least about 100 μM. Combinations of the ranges referenced above (eg, up to about 10 μM and at least about 1 nM) are also within the scope of this disclosure. Other ranges are also possible.

In certain embodiments, the activity of bromodomain-containing proteins is inhibited by compounds described herein. Inhibition of the activity of a bromodomain-containing protein by a compound described herein, when a compound described herein, or a pharmaceutical composition thereof, is contacted with a bromodomain-containing protein. It may be measured by the half-inhibitory concentration (IC ₅₀ ) value of the described compound. In certain embodiments, IC ₅₀ values are obtained by competitive binding assays. In certain embodiments, IC ₅₀ values are obtained by the methods described herein. In certain embodiments, the IC ₅₀ values for the compounds described herein are up to about 1 mM, up to about 300 μM, up to about 100 μM, up to about 30 μM, up to about 10 μM, up to about 3 μM, up to about 1 μM, up to about 300 nM, up to about 100 nM, up to about 30 nM, up to about 10 nM, up to about 3 nM, or up to about 1 nM. In certain embodiments, the IC ₅₀ values for the compounds described herein are at least about 1 nM, at least about 3 nM, at least about 10 nM, at least about 30 nM, at least about 100 nM, at least about 300 nM, at least about 1 μM, at least about 3 μM, at least about 10 μM, at least about 30 μM, at least about 100 μM, at least about 300 μM, or at least about 1 mM. Combinations of the ranges referenced above (eg, up to about 300 μM and at least about 1 μM) are also within the scope of this disclosure. Other ranges are also possible. In certain embodiments, the compounds described herein have an IC ₅₀ value of up to about 300 μM. In certain embodiments, the compounds described herein have an IC ₅₀ value of up to about 30 μM. In certain embodiments, the compounds described herein have an IC ₅₀ value of up to about 10 μM.

Compounds described herein may selectively inhibit the activity of bromodomain-containing proteins. In certain embodiments, the compounds described herein selectively inhibit the activity of a bromodomain-containing protein compared to a different bromodomain-containing protein. In certain embodiments, the compounds described herein selectively inhibit the activity of bromodomain-containing proteins relative to proteins that are not bromodomain-containing proteins. In certain embodiments, the compounds described herein selectively inhibit BET protein. In certain embodiments, compounds described herein selectively inhibit BRD2. In certain embodiments, compounds described herein selectively inhibit BRD3. In certain embodiments, compounds described herein selectively inhibit BRD4. In certain embodiments, the compounds described herein selectively inhibit BRDT. In certain embodiments, compounds described herein selectively inhibit TAF proteins (eg, TAF1 or TAF1L), CBP, and/or EP300. In certain embodiments, the compounds described herein are non-selective inhibitors of two or more bromodomain-containing proteins. In certain embodiments, the compounds described herein are non-selective inhibitors of bromodomain-containing and non-bromodomain-containing proteins.

In certain embodiments, the compounds described herein selectively inhibit the activity of bromodomain-containing proteins compared to kinases (eg, the kinases described herein). In certain embodiments, the compounds described herein inhibit the activity of bromodomain-containing proteins such as MPS1 (TTK), ERK5 (BMK1, MAPK7), polokinase (e.g., polokinase 1, polokinase 2, polokinase 3, polokinase 4), Ack1, Ack2, AbI, DCAMKL1, ABL1, Abl mutant, DCAMKL2, ARK5, BRK, MKNK2, FGFR4, TNK1, PLK1, ULK2, PLK4, PRKD1, PRKD2, PRKD3, ROS 1, RPS6KA6, TA OK1, TAOK3, TNK2, Bcr-Abl, GAK, cSrc, TPR-Met, Tie2, MET, FGFR3, Aurora, AxI, Bmx, BTK, c-kit, CHK2, Flt3, MST2, p70S6K, PDGFR, PKB, PKC, Raf, Selectively inhibits ROCK-H, Rsk1, SGK, TrkA, TrkB, and/or TrkC. In certain embodiments, the compounds described herein selectively inhibit the activity of bromodomain-containing proteins compared to MAP kinase. In certain embodiments, the compounds described herein selectively inhibit the activity of bromodomain-containing proteins compared to mitotic spindle kinase. In certain embodiments, the compounds described herein selectively inhibit the activity of bromodomain-containing proteins compared to polokinase.

The selectivity of the compounds described herein in inhibiting the activity of a bromodomain-containing protein relative to a second protein (e.g., a kinase) that is different from the bromodomain-containing protein inhibits the activity of the bromodomain-containing protein. It may be determined by the quotient of the IC ₅₀ value of a compound described herein in inhibiting the activity of a second protein relative to the IC ₅₀ value of a compound described herein in inhibiting the activity of a second protein. The selectivity of a compound described herein for a second protein with respect to a bromodomain-containing protein is also determined by the K _d value of the adduct of a compound described herein with a bromodomain-containing protein. It may be determined by the quotient of the K _d values of the adduct of the compound and the second protein. In certain embodiments, the selectivity is at least about 1-fold, at least about 2-fold, at least about 3-fold, at least about 5-fold, at least about 10-fold, at least about 30-fold, at least about 100-fold, at least about 300-fold, at least about 1,000 times, at least about 3,000 times, at least about 10,000 times, at least about 30,000 times, or at least about 100,000 times. In certain embodiments, the selectivity is at most about 100,000-fold, at most about 10,000-fold, at most about 1,000-fold, at most about 100-fold, at most about 10-fold, or at most about 1-fold. It is. Combinations of the ranges referenced above (eg, at least about 2 times and up to about 10,000 times) are also within the scope of this disclosure. Other ranges are also possible. In certain embodiments, the selectivity is at least about 3-fold. In certain embodiments, the selectivity is at least about 10-fold. In certain embodiments, the selectivity is at least about 50 times. In certain embodiments, the selectivity is at least about 100-fold. In certain embodiments, the selectivity is at least about 1000 times.

In another aspect, the disclosure provides a method of inhibiting the activity of a bromodomain-containing protein in a subject. In another aspect, the disclosure provides methods of inhibiting the activity of bromodomain-containing proteins in biological samples (eg, cells, tissue samples). In certain embodiments, the bromodomain-containing protein is a bromodomain-containing protein described herein (eg, a BET protein such as BRD2, BRD3, BRD4, or BRDT). In certain embodiments, the activity of a bromodomain-containing protein in a subject or biological sample (eg, a cell) is inhibited in the described methods. In certain embodiments, the activity of a bromodomain-containing protein in a subject or biological sample (e.g., a cell) is at least about 1%, at least about 3%, at least about 10%, at least about 20%, at least about inhibited by up to 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In certain embodiments, the activity of a bromodomain-containing protein in a subject or biological sample (e.g., a cell) is up to about 90%, up to about 80%, up to about 70%, up to about 60%, up to about 50%, up to about 40%, up to about 30%, up to about 20%, up to about 10%, up to about 3%, or up to about 1%. Combinations of the ranges referenced above (eg, at least about 10% and up to about 50%) are also within the scope of this disclosure. Other ranges are also possible. In some embodiments, the activity of a bromodomain-containing protein in a subject or biological sample (eg, a cell) is selectively inhibited in the described methods. In some embodiments, the activity of a bromodomain-containing protein in a subject or biological sample (e.g., a cell) is compared to the activity of a kinase (e.g., MAP kinase, mitotic spindle kinase, polo kinase), selectively inhibited in the described method. In other embodiments, the activity of a bromodomain-containing protein in a subject or biological sample (eg, a cell) is non-selectively inhibited in the described methods. In certain embodiments, cytokine levels and/or histamine release are reduced in the described methods.

In certain embodiments, the activity of the bromodomain-containing protein is an aberrant activity of the bromodomain-containing protein. In certain embodiments, the activity of the bromodomain-containing protein is increased activity of the bromodomain-containing protein. In certain embodiments, the activity of the bromodomain-containing protein is an undesirable activity of the bromodomain-containing protein. In certain embodiments, the activity of bromodomain-containing proteins is reduced in the methods of the present disclosure. Another aspect of the disclosure relates to a method of inhibiting the binding of a bromodomain of a bromodomain-containing protein to an acetyl-lysine residue of a second protein (eg, a histone) in a subject. Another aspect of the disclosure relates to a method of inhibiting the binding of a bromodomain of a bromodomain-containing protein to an acetyl-lysine residue of a second protein (eg, a histone) in a biological sample (eg, a cell). In certain embodiments, the second protein is a protein with an acetyl-lysine residue. In certain embodiments, the second protein is not a bromodomain-containing protein. In certain embodiments, the second protein is a histone. In certain embodiments, the histones are selected from the group consisting of H1, H2A, H2B, H3, H4, and H5. In certain embodiments, binding of a bromodomain of a bromodomain-containing protein to an acetyl-lysine residue of a second protein (eg, a histone) is inhibited in the described methods.

It is known in the art that bromodomain-containing proteins are implicated in a wide variety of diseases. For example, BRD3 and BRD4 relate to BRD3 NUT midline cancer and BRD4 NUT midline cancer, respectively. BRDT relates to spermatogenesis and CBP relates to mixed lineage leukemia (MLL). Accordingly, the compounds described herein are expected to be useful in the treatment and/or prevention of diseases associated with bromodomain-containing proteins or as male contraceptives.

This disclosure relates to diseases associated with bromodomains, diseases associated with bromodomain activity (e.g., abnormal activity), diseases associated with bromodomain-containing proteins, activities of bromodomain-containing proteins (e.g., abnormal activity), ) provides methods for the treatment of a wide range of diseases, including those associated with cancer. Exemplary diseases include, but are not limited to, proliferative diseases, cardiovascular diseases, viral infections, fibrotic diseases, neurological diseases, metabolic diseases, endocrine diseases, and radiotoxicity. Also provided by the present disclosure are methods for male contraception. The disclosure also provides methods of inhibiting spermatogenesis. The disclosure further provides methods for inhibiting the activity (e.g., abnormal activity, such as elevated or undesired activity) of a bromodomain or bromodomain-containing protein, a second protein (e.g. methods of inhibiting the binding of (eg, histones) to acetyl-lysine residues; methods of modulating (e.g., inhibiting) transcriptional elongation; methods of modulating (e.g., inhibiting) the expression (e.g., transcription) of genes regulated by bromodomain-containing proteins; Methods of inducing apoptosis (eg, downregulating or inhibiting), methods of inducing apoptosis, and methods of inducing G1 phase arrest are provided.

Provided herein are methods of treating a disease in a subject in need thereof. In certain embodiments, the disease is associated with bromodomain-containing proteins. In certain embodiments, the disease is associated with bromodomain-containing protein activity. In certain embodiments, the disease is associated with abnormal or increased activity of bromodomain-containing proteins.

In certain embodiments, the disease is associated with bromodomains (eg, bromodomains of bromodomain-containing proteins). In certain embodiments, the disease is associated with bromodomain activity. In certain embodiments, the disease is associated with abnormal, undesirable, or increased activity of bromodomains. In certain embodiments, the disease is associated with bromodomain function (eg, dysfunction).

In certain embodiments, the diseases described herein are driven by transcriptional activators. In certain embodiments, the transcription activator is Myc. In certain embodiments, the disease is associated with NUT rearrangements. In certain embodiments, the disease is associated with aberrant Myc function. In certain embodiments, the disease is associated with interleukin 7 receptor (IL7R).

In certain embodiments, the disease is a proliferative disease (eg, a proliferative disease described herein). In certain embodiments, the disease is cancer (eg, a cancer described herein). In certain embodiments, the disease is lung cancer. In certain embodiments, the disease is multiple myeloma. In certain embodiments, the disease is neuroblastoma. In certain embodiments, the disease is colon cancer. In certain embodiments, the disease is testicular cancer. In certain embodiments, the disease is ovarian cancer. In certain embodiments, the disease is lung cancer (eg, small cell lung cancer or non-small cell lung cancer). In certain embodiments, the disease is NUT midline cancer (eg, BRD3 NUT midline cancer or BRD4 NUT midline cancer). In certain embodiments, the disease is leukemia. In certain embodiments, the disease is mixed lineage leukemia (MLL). In certain embodiments, the disease is acute myeloid leukemia (AML), mixed B myelomonocytic leukemia, or erythroleukemia. In certain embodiments, the disease is selected from the group consisting of Burkitt's lymphoma, cancer of the breast, colon cancer, neuroblastoma, glioblastoma polymorphism, chronic lymphocytic leukemia, and squamous cell carcinoma. .

In certain embodiments, the disease is a benign neoplasm (eg, a benign neoplasm described herein).

In certain embodiments, the disease is an inflammatory disease (eg, an inflammatory disease described herein). In certain embodiments, the disease is a disease that involves an inflammatory response to bacterial, viral, fungal, parasitic, and/or protozoal infection. In certain embodiments, the disease is osteoarthritis, acute gout, multiple sclerosis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), neuroinflammation, asthma, chronic obstructive airway disease, pneumonia, Myositis, eczema, dermatitis, acne, cellulitis, obstructive disease, thrombosis, alopecia, nephritis, vasculitis, retinitis, uveitis, scleritis, sclerosing cholangitis, hypophysitis, thyroiditis, septic shock, systemic inflammatory response syndrome (SIRS), toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, burns, pancreatitis (for example, acute pancreatitis), post-operative syndrome, sarcoidosis, selected from the group consisting of Herxheimer reaction, encephalitis, myelitis, meningitis, and malaria. In certain embodiments, the disease is acute or chronic pancreatitis. In certain embodiments, the disease is a burn injury. In certain embodiments, the disease is inflammatory bowel disease. In certain embodiments, the disease is neuroinflammation. In certain embodiments, the disease is sepsis or sepsis syndrome. In certain embodiments, the disease is graft-versus-host disease (GVHD).

In certain embodiments, the disease is an autoimmune disease (eg, an autoimmune disease described herein). In certain embodiments, the disease is rheumatoid arthritis. In certain embodiments, the disease is psoriasis, systemic lupus erythematosus, vitiligo, a bullous skin disease.

In certain embodiments, the disease is a cardiovascular disease. In certain embodiments, the disease is atherogenesis or atherosclerosis. In certain embodiments, the disease is arterial stent occlusion, heart failure (e.g., congestive heart failure), coronary artery disease, myocarditis, pericarditis, valvular heart disease, stenosis, restenosis, in-stent stenosis, angina, myocardial infarction, acute coronary syndrome, coronary artery bypass grafting, cardiopulmonary bypass, endotoxemia, ischemia-reperfusion injury, cerebrovascular ischemia (stroke), renal reperfusion injury, embolism (e.g., pulmonary, renal, liver, gastrointestinal, or distal extremity embolism) or myocardial ischemia.

In certain embodiments, the disease is a viral infection. In certain embodiments, the disease is an infection caused by a DNA virus. In certain embodiments, the disease is an infection caused by a dsDNA virus. In certain embodiments, the disease is an infection caused by an ssDNA virus. In certain embodiments, the disease is an infection caused by an RNA virus. In certain embodiments, the disease is an infection caused by a dsRNA virus. In certain embodiments, the disease is an infection caused by a (+)ssRNA virus. In certain embodiments, the disease is an infection caused by a (-)ssRNA virus. In certain embodiments, the disease is an infection caused by a reverse transcription (RT) virus. In certain embodiments, the disease is an infection caused by an ssRNA-RT virus. In certain embodiments, the disease is an infection caused by a dsDNA-RT virus. In certain embodiments, the disease is an infection caused by human immunodeficiency virus (HIV). In certain embodiments, the disease is an infectious disease caused by acquired immunodeficiency syndrome (AIDS). In certain embodiments, the disease is an infection caused by human papillomavirus (HPV). In certain embodiments, the disease is an infection caused by hepatitis C virus (HCV). In certain embodiments, the disease is an infection caused by a herpesvirus (eg, herpes simplex virus (HSV)). In certain embodiments, the disease is an infection caused by Ebola virus. In certain embodiments, the disease is an infectious disease caused by Severe Acute Respiratory Syndrome (SARS). In certain embodiments, the disease is an infection caused by influenza virus. In certain embodiments, the disease is an infection caused by influenza virus. In certain embodiments, the disease is an infection caused by influenza A virus. In certain embodiments, the disease is human influenza (eg, human influenza caused by H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3, or H10N7 viruses). In certain embodiments, the disease is avian influenza (eg, avian influenza caused by H5N1 or H7N9 viruses). In certain embodiments, the disease is swine influenza (eg, swine influenza caused by H1N1, H1N2, H2N1, H3N1, H3N2, H2N3, or influenza C viruses). In certain embodiments, the disease is equine influenza (eg, equine influenza caused by H7N7 or H3N8 viruses). In certain embodiments, the disease is canine influenza (eg, canine influenza caused by the H3N8 virus). In certain embodiments, the disease is an infection caused by an influenza B virus. In certain embodiments, the disease is an infection caused by influenza C virus. In certain embodiments, the disease is an infection caused by dengue fever, dengue hemorrhagic fever (DHF), dengue shock syndrome (DSS), hepatitis A, hepatitis B, hepatitis D, hepatitis E, hepatitis F, Coxsackie A virus. infections caused by coxsackie B virus, fulminant viral hepatitis, viral myocarditis, infections caused by parainfluenza virus, infections caused by respiratory syncytial virus (RSV) (e.g., RSV bronchiolitis, RSV pneumonia, especially infections caused by RSV in infants and children and RSV pneumonia in patients with cardiopulmonary disease), infections caused by measles virus, infections caused by vesicular stomatitis virus, infections caused by rabies virus, Japanese encephalitis, Infection caused by Junin virus, Infection caused by human cytomegalovirus, Infection caused by Baricerovirus, Infection caused by cytomegalovirus, Infection caused by Muromegalovirus, Probosci Infections caused by viruses, Infections caused by Roseolovirus, Infections caused by Lymphocryptovirus, Infections caused by Macavirus, Infections caused by Perchavirus, Infections caused by Radinovirus. infection caused by poliovirus, infection caused by Marburg virus, infection caused by Lassa fever virus, Venezuelan equine encephalitis, infection caused by Rift Valley fever virus, infection caused by Korean hemorrhagic fever virus , infections caused by the Crimean-Congo hemorrhagic fever virus, encephalitis, Saint Louise encephalitis, Kyasanur Forest disease, Murray Valley encephalitis, tick-borne encephalitis, West Nile encephalitis, yellow fever, infections caused by adenoviruses, by poxviruses is an infectious disease caused or a viral infection in an immunocompromised subject.

In certain embodiments, the disease is a fibrotic condition. In certain embodiments, the disease is selected from the group consisting of renal fibrosis, postoperative stenosis, keloid formation, cirrhosis, biliary cirrhosis, and myocardial fibrosis. In certain embodiments, the disease is scleroderma. In certain embodiments, the disease is idiopathic pulmonary fibrosis.

In certain embodiments, the disease is an endocrine disease. In certain embodiments, the disease is Addison's disease.

In certain embodiments, the disease is a neurological disease (eg, Alzheimer's disease).

In certain embodiments, the disease is a metabolic disease. In certain embodiments, the disease is diabetes. In certain embodiments, the disease is type I diabetes. In certain embodiments, the disease is type II diabetes or gestational diabetes. In certain embodiments, the disease is obesity. In certain embodiments, the disease is hepatic steatosis (NASH or other), cachexia, hypercholesterolemia, or a disorder of lipid metabolism through the regulation of apolipoprotein A1 (APOA1).

In certain embodiments, the disease is radiotoxicity. In certain embodiments, the disease is radiation damage.

In certain embodiments, the disease is acute rejection of a transplanted organ or multiple organ dysfunction syndrome.

In yet another aspect, the disclosure provides methods for preventing the diseases described herein in a subject in need thereof. The present disclosure also provides methods for reducing the risk of developing a disease described herein in a subject in need thereof.

In another aspect, the disclosure provides a method for providing male contraception in a male subject in need thereof.

In yet another aspect, the disclosure provides a method of inhibiting spermatogenesis in a subject in need thereof.

Another aspect of the disclosure relates to a method of inhibiting viral replication. In certain embodiments, viral replication is inhibited by the methods described. In certain embodiments, the virus is in vitro. In certain embodiments, the viruses described herein are present ex vivo. In certain embodiments, the virus is in vivo. Another aspect of the disclosure relates to a method of killing a virus. In certain embodiments, the virus is killed by the methods described.

In certain embodiments, the methods of treatment and/or prophylaxis provided herein provide a method of treatment and/or prevention to a subject in need thereof of formula (I), (II), (III), (IV), (V), or The compound represented by (VI), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, cocrystal, tautomer, stereoisomer, isotope-labeled derivative, or prodrug thereof , or a pharmaceutical composition thereof. In certain embodiments, a therapeutically effective amount of a compound described herein is administered to a subject. In certain embodiments, a prophylactically effective amount of a compound described herein is administered to a subject.

In certain embodiments, the subject is an animal. Animals may be of either sex and at any stage of development. In certain embodiments, the subject is male. In certain embodiments, the subject is female. In certain embodiments, a subject described herein is a human. In certain embodiments, the subject described herein is a human male. In certain embodiments, a subject described herein is a human female. In certain embodiments, the subject is a human diagnosed with a disease described herein. In certain embodiments, the subject is a human who has been diagnosed as being at higher than normal risk of developing a disease described herein. In certain embodiments, the subject is a human suspected of having a disease described herein. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a fish. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a human or non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (eg, mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (eg, a transgenic mouse and a transgenic pig).

In certain embodiments, the cells described herein are in vitro. In certain embodiments, the cells are ex vivo. In certain embodiments, the cells are in vivo.

In another aspect, the disclosure provides methods of modulating (eg, inhibiting) transcription elongation. In certain embodiments, transcription elongation is modulated (eg, inhibited) in the described methods. In certain embodiments, the method comprises administering to a subject a compound described herein, or a salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the method includes contacting a cell or biological sample with a compound described herein, or a salt thereof, or a pharmaceutical composition thereof.

In another aspect, the disclosure provides a method of modulating the expression (eg, transcription) of a gene regulated by a bromodomain-containing protein in a subject. In another aspect, the disclosure provides methods of modulating the expression (eg, transcription) of genes regulated by bromodomain-containing proteins in a biological sample (eg, cells, tissues). In certain embodiments, the method comprises administering to a subject a compound described herein, or a salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the method includes contacting a cell or biological sample with a compound described herein, or a salt thereof, or a pharmaceutical composition thereof.

In certain embodiments, the present disclosure provides methods for downregulating or inhibiting the expression (e.g., transcription) of genes regulated by bromodomain-containing proteins in a subject or biological sample (e.g., cells, tissues). do. Without wishing to be bound by any particular theory, the compounds and pharmaceutical compositions described herein are capable of interfering with the binding of bromodomain-containing proteins to transcription initiation sites of genes. You can. In certain embodiments, the compounds and pharmaceutical compositions described herein interfere with the recognition of acetyl-lysine by bromodomains or bromodomain-containing proteins during gene expression (eg, transcription). In certain embodiments, the compounds and pharmaceutical compositions described herein provide anchoring of bromodomain-containing proteins to acetylated chromatin (e.g., acetylated chromatin) during gene expression (e.g., transcription). It interferes with the bromodomains of bromodomain-containing proteins that are anchored to acetyl-lysine in chromatin. In certain embodiments, the expression (eg, transcription) of a gene regulated by a bromodomain-containing protein in a subject or biological sample (eg, a cell) is modulated in the described methods. In certain embodiments, expression (eg, transcription) of a gene regulated by a bromodomain-containing protein in a subject or biological sample (eg, a cell) is downregulated or inhibited in the described methods. In certain embodiments, the gene regulated by the bromodomain-containing protein is an oncogene.

Another aspect of the disclosure relates to a method of inhibiting the interaction between a bromodomain-containing protein and an immunoglobulin (Ig) regulatory element in a subject. Another aspect of the present disclosure relates to methods of inhibiting interactions between bromodomain-containing proteins and immunoglobulin (Ig) regulatory elements in a biological sample (eg, a cell). In certain embodiments, the method comprises administering to a subject a compound described herein, or a salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the method includes contacting a biological sample with a compound described herein, or a salt thereof, or a pharmaceutical composition thereof.

Another aspect of the present disclosure relates to methods of inhibiting interactions between bromodomain-containing proteins and immunoglobulin (Ig) regulatory elements in a biological sample (eg, a cell). Another aspect of the present disclosure relates to a method of inducing apoptosis in cells of a biological sample (eg, in vitro cells, cancer cells). In certain embodiments, a method for inducing apoptosis in a subject comprises administering to the subject a compound described herein, or a salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the method of inducing apoptosis in a biological sample (eg, a cell) comprises contacting the biological sample with a compound described herein, or a salt thereof, or a pharmaceutical composition thereof.

Another aspect of the disclosure relates to methods of inducing G1 phase arrest in cells of a subject. Another aspect of the present disclosure relates to a method of inducing G1 phase arrest in cells of a biological sample. In certain embodiments, the method comprises administering to a subject a compound described herein, or a salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the method includes contacting a cell or biological sample with a compound described herein, or a salt thereof, or a pharmaceutical composition thereof.

In certain embodiments, the methods of the present disclosure include administering an effective amount of a compound or pharmaceutical composition described herein to a subject in need thereof. In certain embodiments, the methods of the present disclosure include administering a therapeutically effective amount of a compound or pharmaceutical composition described herein to a subject in need thereof. In certain embodiments, the methods of the present disclosure include administering a prophylactically effective amount of a compound or pharmaceutical composition described herein to a subject in need thereof. In certain embodiments, the methods of the present disclosure include contacting a biological sample (eg, a cell) with an effective amount of a compound or pharmaceutical composition described herein. In certain embodiments, the methods of the present disclosure include contacting a virus with an effective amount of a compound or pharmaceutical composition described herein.

In another aspect, the present disclosure provides a compound described herein for use in a method of the present disclosure, or for use in the manufacture of a medicament for use in a method or treatment described herein. I will provide a.

In yet another aspect, the present disclosure provides the use of a compound described herein for use in a method of the present disclosure, or for use in the manufacture of a medicament for use in a method or treatment described herein. A pharmaceutical composition is provided.

In yet another aspect, the invention provides the use of the described compounds, or pharmaceutical compositions thereof, for the manufacture of a medicament for the treatment of the diseases discussed herein.

EXAMPLES These and other aspects of the invention will be further understood in consideration of the following examples. The examples are intended to illustrate certain specific aspects of the invention and are not intended to limit its scope as defined in the claims.

Potent and Selective Bivalent Inhibitors of BET Family Bromodomains Bivalent inhibitors of BRD4 were designed, prepared, and evaluated. Previous high-resolution structures of JQ1 bound to BD1 and BD2 (see, for example, Filippakopoulos, P. et al. Nature 2010, 468, 1067-1073) and internal structure-activity relationships. ) (SAR) guidelines for both the chemical substitution of the bulky t-butyl ester functionality at C6 on the diazepine ring and the substitution of the methyl moiety at C2 on the thiophene ring. These results are supported by the fact that the Because the BD1 and BD2 bromodomains are separated by a 280-residue linker region (Fig. 1c), and because the binding can be intramolecular or intermolecular, the chemical spacer between the monomeric ligands It was considered a variable for the synthesis of focused libraries. Because only limited biochemical data are available for full-length BRD4, and because of the challenges in preparing active proteins, the manner in which the linker is attached to the monomeric ligand has been evaluated using an index library. ) was further considered in the design. Initially, a series of three dimeric molecules were prepared, defined by the conjugation of variably spaced polyethylene glycol (PEG) linkers to either the C6 or C2 position. These are hereinafter referred to as (6+6), (2+2), and (6+2) (Fig. 1d).

First, (6+6) and (2+2) homodimers with minimal PEG spacers were synthesized (Figures 2a and 2b). These compounds were compared to control ligands in biochemical and cell-based assays of direct BRD4 inhibition. A luminescence homogeneous, nanomaterial-based proximity assay was adapted to BRD4(1) as a primary screening method to assess competitive binding of JQ1 to the BET bromodomain. (AlphaScreen™) (see e.g. McKeown, MR et al. Journal of Medicinal Chemistry 2014, 57, 9019-9027; Roberts, JM & Bradner, JE Current protocols in chemical biology 2015, 7, 263-278 ). For the synthesis of the (2+2) homodimer, a methyl ester analog of JQ1 (MS417, Figure 1a) was adapted as a scaffold replacement. In this assay system, the active (S)-enantiomer of JQ1 exhibited an IC ₅₀ of 21 nM (Figure 6). In contrast, the IC ₅₀ of the inactive (R)-enantiomer was >5 μM. The growth effects of BRD4 inhibition were evaluated using BRD4-rearranged cancer cells (so-called NUT midline carcinoma; NMC797) and an acute myeloid leukemia (AML) cell line (MV4; 11). (S)-JQ1 attenuated the proliferation of each cell line with IC ₅₀ values of 69 nM and 72 nM, respectively. MS417 showed similar levels of inhibition in both AlphaScreen™ and cells (Figure 1a).

The (6+6) homodimer with a PEG1 linker (hereinafter referred to as (6+6)-PEG1) did not show improved activity in either biochemical or cellular assays (Fig. 2a). Interestingly, the (2+2) homodimer, (2+2)-PEG1, had a 20-fold increased biochemical potency (IC ₅₀ =1.17 nM) (Figure 2b). However, this effect was not accurately reflected in cellular activity. This is probably due to the reduced permeability resulting from the two ester moieties being added. To overcome these challenges, we focused on (6+2) heterodimers with various PEG linker lengths. These molecules feature a single C6 ester (Figure 3a). Remarkably, all of the (6+2) heterodimers we synthesized showed significant improvement in potency (IC ₅₀ values from single order of magnitude to sub-nanomolar) in biochemical assays. (Figure 7). Similar results were obtained with another BET family protein BRDT (1) (Fig. 3c). Importantly, the increased biochemical potency was maintained in cellular assays (IC ₅₀ =0.22-2.6 nM). All (6+2)-PEG1 diastereomers were synthesized (Figure 3b) to ignore non-specific assay interferences from compounds (e.g. aggregation) (e.g. Dahlin, JL et al. Journal of medicinal chemistry 2015, 58, 2091-2113). While only the homo-combination of the active (S)-enantiomer of JQ1 retained single-digit to sub-nanomolar activity in both biochemical and cellular assays; The homodimer of inactive (R)-JQ1 showed much weaker activity (IC ₅₀ =5,956 nM by AlphaScreen™). The hetero-combinations of (S)- and (R)-JQ1 ((6S+2R)-PEG1 and (6R+2S)-PEG1) retain almost the same level of activity as JQ1 in biochemical assays. (IC ₅₀ =59 nM and 103 nM, respectively). This suggests the ability to conjugate a linker at either the C2 or C6 position. Collectively, these data support dramatic enhancement of BRD4 binding by bivalent inhibitors in biochemical and cellular assays.

Fluorescent polarization (FP) and phage-based, multiplexed bromodomain displacement assays (BROMOscan™, DiscoveRx) to further profile bivalent inhibitors was used. All analogs showed some increase in the sensitivity of the BROMOscan™ assay to JQ1 compared to AlphaScreen™ (for BRD4(1), BROMOscan™, K _d =8.0 nM; AlphaScreen™ ), IC ₅₀ =20.9 nM), showed a similar trend in the FP assay (Figure 3c). This tendency was more pronounced in the case of (6S+2S)-PEG1 (Figure 3d). Compounds can be used in picomolar forms of phages expressing BRD4(1), BRD4(2), a tandem bromodomain construct (BRD4(1,2)), and a full length protein (BRD4(full)). Displacement was presented. These dramatic increases in activity were confirmed as selective for the BET family using a panel of 32 phage-displayed bromodomains (Table S1). The (6S+2S)-PEG1 compound showed no significant binding to non-BET family bromodomains at higher concentrations (K _d = 2.5 μM for CBP, 5.0 μM for EP300, WDR9 (2 ), 9.9 μM in other cases >10 μM). The relative selectivity of the JQ1 backbone is reflected in this JQ1 dimer.

To establish bivalent BET inhibition using an orthogonal chemical scaffold, the most recently reported isoxazole BET inhibitor, I-BET151, was adapted to a homodimeric strategy (as an example , Dawson, M. A. et al. Nature 2011, 478, 529-533). I-BET151 exhibited comparable performance to JQ1 in biochemical and cellular assays (Figure 6). The reported co-crystal structure of I-BET151 bound to BRD4(1) shows that the isoxazole ring binds to the conserved asparagine, while the amino moiety within the cyclic urea faces the solvent-exposed region. are doing. The hetero- and homodimeric combination of I-BET151 and JQ1 was resynthesized using a series of PEG linkers (Figure 8). Impressively, a 5-fold increase in biochemical inhibition was observed in some combinations.

Bivalent Inhibitors Bind to Two Kac-Binding Sites on BET Family Bromodomains To determine whether the observed increased potency was mediated by bivalent interactions with two bromodomains separated by size Exclusion chromatography (SEC) and isothermal titration calorimetry (ITC) were employed. SEC completely shifts the BRD4(1) monomeric form peak to a slower migrating dimeric form peak when activated (6S+2S)-PEG1 molecules are added at a 1:2 ratio to protein. However, excess JQ1 and inactive (6R+2R)-PEG1 molecules failed to shift the monomer peak (Fig. 4a). Experimentally, no obvious signs of protein aggregation were observed. As expected, ITC experiments revealed that JQ1 and (6S+2S)-PEG1 bound to isolated BRD4(1) with a similar range of K _d values (40 nM and 17 nM, respectively). Ta. However, the stoichiometry of binding was different. JQ1 bound to BRD4(1) in a 1:1 ratio, whereas (6S+2S)-PEG1 bound to BRD4(1) in a 1:2 ratio (Fig. 4b). Collectively, these findings support the possibility of avidity effects via dimerization of individual BET bromodomains.

Bivalent inhibitor induces growth arrest in AML cells associated with MYC down-regulation and HEXIM1 up-regulation Next, a series of cancer cell assays using JQ1 (these were The cellular consequences of bivalent BET inhibitors were assessed in previously credentialed for BRD4-specific biology. To assess whether cell growth inhibition by (2S+6S)-PEG1 is mediated through downregulation of MYC transcription as observed with JQ1, the expression levels of MYC and HEXIM1 after compound treatment were measured by immunoblotting. . Within 2 hours of treatment with (2S+6S)-PEG1 in MV4;11 cells, MYC was down-regulated in a concentration-dependent manner at concentrations as low as 10 nM (Fig. 4c). This effect was time-dependent and reversible (Fig. 4d), reaching maximum effect at 2 hours. Consistent with an inhibitory effect on transcriptional elongation, upregulation of the compensatory negative elongation factor HEXIM1 was observed at later time points (4-24 hours). Taken together, these data support on-target BRD4 activity in cells (e.g., Chaidos, A. et al. Blood 2014, 123, 697-705; Bartholomeeusen, K et al. The Journal of biological chemistry 2012, 287, 36609-36616).
A highly potent compound capable of degrading BET bromodomain proteins through chemical conjugation of phthalimide that recruits E3 ligase has recently been reported. Immunoblots were performed following compound treatment to ignore enhanced efficacy via BET degradation (e.g., Winter, GE et al. Science (New York, NY) 2015, 348, 1376-1381, doi :10.1126/science.aab1433). No effect was observed on protein stability, suggesting that the effect is not likely due to oligomerization and subsequent BRD4 degradation in the cells. These findings confirm that cell growth inhibition by (2S+6S)-PEG1 was associated with specific BRD4 involvement.

MT1: Bivalent chemical probe of BET bromodomain JQ1 has acceptable pharmacokinetic (PK) properties in animal studies, but the heterodimer (2S+6S) had a short plasma half-life in vivo. Perhaps this suggests that the metabolization of the newly introduced linker section has been prolonged (see for example Matzuk, MM et al. Cell 2012, 150, 673-684). Therefore, biostable derivatives were sought to support their use as chemical probes in vivo. During linker optimization, a homodimeric (6S+6S) derivative with a long PEG7 linker (hereafter referred to as MT1) was found to have an activity comparable to that of the previously explored heterodimeric molecule (BRD4(1)). ), it was clear that the PK properties were improved (FIGS. _5a and 10a). MT1 does not possess metabolically susceptible ester moieties. It is also noteworthy that the heterodimer (6S+2S) with a short "PEG0" (ethylenediamine) linker has comparable PK properties to MT1 (Figure 10b). The biochemical activity of MT1 was well translated into cellular activity (Fig. 5e), which prompted us to further profile this molecule. MT1 exhibits off-target effects on few of the more than 50 cellular receptors and ion channels tested. Similar to the parent scaffold JQ1, only partial inhibition of [Nleu-10]-NKA radioligand agonist binding to the neurokinin NK2 receptor was observed (Figures 15 and 21) (e.g., Filippakopoulos , P. et al. Nature 2010, 468, 1067-1073). These data led to further profiling of MT1.

To assess whether MT1 dimerizes monomeric BET bromodomains, we used the AlphaScreen™ assay to perform ligand-induced proximalization of two differently tagged BRD4(1) constructs. It was adapted to estimate (proximity). When GST-BRD4(1) and His-BRD4(1) constructs were introduced together with MT1, luminescence transfer was observed between GSH-donor and nickel-acceptor beads. An increase in signal over baseline levels was observed in the submicromolar range (Fig. 5b). The luminescence signal decreased at higher concentrations, which is characteristic of the Hook effect seen with multivalent inhibitors (see, for example, Dutta Roy, R. & Stefan, M. I. bioRxiv (see 2015).

To establish the binding mode of MT1, co-crystal structures of the ligand in complex with purified recombinant BRD4 (1) and BRD4 (2) were analyzed. A co-crystal structure of BRD4(2) was successfully obtained when excess MT1 was added (Fig. 5c, Fig. 5d, and Fig. 17). See Figure 22 for data collection and refinement statistics. Similar high concentrations of MT1 were incompatible with the crystallization of BRD4(1). The determined high-resolution structure clearly revealed one molecule of MT1 and simultaneously recognized two bromodomains of BRD4(2) (Fig. 5c). Binding of MT1 established a newly created hydrophobic pocket between the two bromodomain monomers (Fig. 5d). Overall, the binding mode of each practical warhead is very similar to that of JQ1 in BRD4 (1) (for example, Filippakopoulos, P. et al. Nature 2010, 468, 1067-1073 ). Each triazole ring formed hydrogen bonds with the evolutionarily conserved asparagine and exhibited high topological complementarity with the Kac binding site occupying the entire binding pocket. On the other hand, these findings support a bromodomain dimerization-based avidity effect on the efficacy of MT1.

SEC was again employed to assess whether MT1 bound intra- or intermolecularly to BRD4. This time, either wild type or with a point mutation (N140A in BRD4(1) and N433A in BRD4(2)) at one of the key conserved asparagine residues in each bromodomain binding pocket. We used tandem bromodomain constructs that were either of the following. The latter is thereby unable to bind to JQ1. Complete dimerization was observed in the second bromodomain mutant (BRD4(1,2 ^MUT )) when half an equivalent amount of MT1 was added. In contrast, there was no dimerization when wild type BRD4(1,2) protein was used. Similarly, partial dimerization was observed in the BRD4( ^1MUT ,2) construct (Fig. 5h). These results support the model that MT1 binds intramolecularly to tandem bromodomains and that both BRD4(1) and BRD4(2) are directly involved in this binding event. .

To establish the target engagement of MT1 in a cellular context, we performed a cellular thermal shift assay (CETSA) (see, for example, Martinez Molina, D. et al. Science 2013, 341, 84-87, doi:10.1126/science.1233606). In the CETSA assay, cells were treated with vehicle or drug and heated to denature, precipitate, and lyse proteins. Cell debris and aggregates are separated from the soluble protein fraction by centrifugation. Unbound proteins denature and precipitate at high temperatures, but proteins bound to the ligand remain in solution. Stabilized proteins in the supernatant were measured by quantitative immunoblotting. Both JQ1 and MT1 stabilized BRD2, 3 and 4 in a concentration-dependent manner, but MT1 was able to bind and stabilize BET protein at lower concentrations (Figure 5i and Figure 18) . These results effectively demonstrate the involvement of BET family proteins as cellular targets of MT1.

Finally, the effect of MT1 on cancer cell viability was assessed. Significant apoptosis was observed by caspase 5 and PARP cleavage after treatment with MT1 (Fig. 5f). These cellular events were followed by upregulation of HEXIM1 and downregulation of MYC. Early and late apoptosis was assessed with Annexin V and propidium iodide staining to compare apoptosis induction between MT1 and JQ1 (Fig. 5g and Fig. 11). Importantly, MT1 induced a greater degree of apoptosis at a 10-fold lower concentration than JQ1.

MT1 has high targeting potency in homogeneous and cellular assays, a well-characterized profile of selectivity, and synthetic accessibility. (for the synthetic scheme of MT1, see Figure 23) possessing all desirable qualities of chemical probes and/or therapeutic agents (see, for example, Arrowsmith, C. H. et al. Nature chemical biology 2015, 11, 536-541, doi:10.1038/nchembio.1867).

Antitumor Efficacy of MT1 in Xenograft Models of Leukemia To determine whether MT1, as a single agent, was able to attenuate the growth of BRD4-dependent leukemia in vivo, aggressive disseminated (aggressive disseminated) leukemia model (mCherry ⁺ , Luciferase ⁺ , MV4; 11) and used equimolar (44.2 μmol/kg) and semi-equivalent (22.1 μmol/kg) MT1 compared to JQ1. Animals with established disease were treated for 14 days. Throughout this study, leukemic burden was monitored by non-invasive bioluminescence imaging. Even half-equivalent MT1 significantly reduced leukemia burden compared to either vehicle or JQ1 during this study (Figure 13a). Post hoc analysis of leukemia burden in bone marrow by FACS also revealed that MT1 administration at 22.1 μg/kg significantly reduced mCherry ⁺ disease (Figure 13b).

We used a similar xenograft model in which mice were treated with equimolar concentrations (44.2 μmol/kg) of JQ1 and MT1 for 12 days to demonstrate that the survival advantage conferred by MT1 could be reversed by JQ1 or MT1. A second study was conducted to assess against vehicle. After a 2-day drug holiday, we continued treatment for another 5 days. At this high dose of drug, 2 mice (out of 11) in the MT1 group had to be sacrificed due to weakness from drug toxicity. Drug administration was stopped after this point and survival of the remaining mice was monitored. It is noteworthy that those mice that lost weight on MT1 regained weight after weaning off the drug (Figure 19). As before, disease monitored by bioluminescence was significantly reduced with treatment of MT1 compared to JQ1 (Figure 13c, Figure 13d). Importantly, MT1 significantly increased overall survival compared to mice treated with vehicle or JQ1 (Figure 13e).

There is a need to develop qualified probes for transcriptional and epigenetic proteins. Among these, potential targets are epigenetic reader proteins that function through protein-protein interactions with post-translationally modified chromatin and transcription factors. Although inhibitors of individual protein-protein interactions have historically been difficult to recognize, epigenetic leader proteins generally possess multivalent recognition modules.

A structural hypothesis regarding multivalent recognition of BET family bromodomain proteins by divalent organic ligands was tested. The heterodimeric derivatives showed greatly improved activity not only biochemically but also in cells with little dependence on linker length. The improved activity of the heterodimeric compounds is likely due to their ability to dimerize bromodomains, as evidenced by SEC, ITC, and nanomaterial-based proximity assays. These bivalent inhibitors have remarkable efficacy and fast kinetic downregulation of MYC in cultured human cancer cells, which makes the drugs more likely to proceed to human clinical investigation. establish a rationale for drug-like derivatives. Indeed, the best optimized bivalent inhibitor MT1 exhibits a 400-fold improvement in activity in AML and a significantly prolonged exposure in vivo compared to JQ1. Although MT1 is rather large (molecular weight 1134 Da) for a classical small molecule inhibitor, it is noteworthy that improvements in metabolic stability and PK properties are achieved by varying the linker length and point of attachment. This chemical modification resulted in a selective and highly potent chemical probe that outperformed JQ1 in leukemia models in vivo.

General Methods Cell Culture MV4;11 cells were purchased from ATCC and NMC797 cells were a kind gift from Dr. Christopher French (Brigham and Women's Hospital). This has been described previously (see, for example, French, CA et al. J Clin Oncol 2004, 22, 4135-4139, doi:10.1200/JCO.2004.02.107). Cells were grown in either DMEM (NMC797) or RPMI1640 (MV4; 11) supplemented with 10% FBS (Sigma), 100 U/mL penicillin, 100 μg/mL streptomycin, and 2 mM glutamine (Gibco) with ₅ % CO Cultured at 37°C. Cells were tested negative for mycoplasma using the MycoAlert™ kit (Lonza). None of the cell lines utilized were among those commonly misidentified as listed by ICLAC.

AlphaScreen(TM) for BRD4(1) and BRDT(1)
The assay was performed with minimal modifications from the manufacturer's protocol (PerkinElmer, USA). All reagents were diluted in AlphaScreen™ buffer (50mM HEPES, 150mM NaCl, 0.1% (w/v) BSA, 0.01% (w/v) Tween20, pH 7.5) and applied to the plate. Allowed to equilibrate to room temperature before addition. After addition of Alpha beads to the master solution, all subsequent steps were performed under low light conditions. Components with final concentrations of His-BRD4 (1) or His-BRDT (1) at 40 nM (see protein expression section), Ni-coated Acceptor Bead at 10 μg/ml, and 20 nM biotinylated JQ1. The 2× solution was added in 10 μL to a 384-well plate (AlphaPlate-384, PerkinElmer) (see for example Anders, L. et al. Nature biotechnology 2014, 32, 92-96). The plate was spun down at 150 xg and 100 nL of compound in DMSO from the stock plate was added by pin transfer using a Janus Workstation (PerkinElmer). Streptavidin-coated donor beads (10 μg/ml final) were added as before in 2× 10 μL volumes. Following this addition, the plates were sealed with foil to prevent light exposure and evaporation. The plate was spun down again at 150 xg. Plates were incubated for 1 hour at room temperature and then read on an Envision 2104 (PerkinElmer) using the manufacturer's protocol.

AlphaScreen(TM) of BRD4(1) dimerization
The assay was performed with minimal modifications from the manufacturer's protocol (PerkinElmer, USA). All reagents were diluted in AlphaScreen™ buffer (50mM HEPES, 150mM NaCl, 0.1% (w/v) BSA, 0.01% (w/v) Tween20, pH 7.5) and applied to the plate. Allowed to equilibrate to room temperature before addition. After addition of Alpha beads to the master solution, all subsequent steps were performed under low light conditions. A 2x solution of the components with final concentrations of His-BRD4(1) (see Protein Expression) and GST-BRD4(1) (BPS Biosciences) at 40 nM was added in 10 μL to a 384-well plate (AlphaPlate-384, PerkinElmer ) was added. The plate was spun down at 150×g and 100 nL of compound in DMSO from the stock plate was added by pin movement using a Janus Workstation (PerkinElmer). Plates were allowed to incubate for 30 minutes before addition of Ni-coated Acceptor Beads and GSH-coated Donor Beads in 2× 10 μL volumes as before. Following this addition, the plates were sealed with foil to prevent light exposure and evaporation. The plate was spun down again at 150 xg. Plates were incubated for 30 minutes at room temperature and then read on the Envision 2104 (PerkinElmer) using the manufacturer's protocol. Data were analyzed using GraphPad PRISM v6 and IC ₅₀ values were determined using the "log(inhibitor) vs. normalized response - variable slope" analysis module.

BRD4(1) Fluorescence Polarization Assay In a 384-well black plate (Nunc), 250 nM His-BRD4(1) (see Protein Expression section) and 20 nM JQ1-FITC were mixed in 20 uL assay buffer containing competitor compound or DMSO ( 50mM HEPES, 150mM NaCl, 0.01% (w/v) Tween20, pH 7.5). Following 30 min incubation at RT, fluorescence polarization (mP) was detected using an Envision 2104 Multilabel Reader (FP FITC dual optical module; excitation: 480 nm, emission: 535 nm for both S- and P-channels). Measured using. Normalized mP values were calculated by setting the average background (wells without enzyme) to 0% average DMSO wells for 100% activity. Standard deviations were determined from four replicate measurements for each compound concentration. Data were analyzed and plotted using GraphPad PRISM v6, and IC ₅₀ values were determined using the "log(inhibitor) vs. normalized response - variable slope" analysis module.

Analysis of cell viability by ATPLite Cells were plated at 1000 cells/well in 50 μL/well of medium in 384-well white culture plates (Thermo). NMC797 cells were allowed to adhere overnight before adding 100 μL of compounds in DMSO from compound stock plates using a Janus Workstation pin tool (PerkinElmer, USA). After addition of compounds, plates were incubated at 37°C for 72 hours. Cell viability was read using the ATPlite kit (PerkinElmer). Plates were brought to room temperature prior to reagent addition. The lyophilized powder was resuspended in lysis buffer and diluted 1:2 with DI water. 20 μL of this solution was added to each well and the plate was incubated for 15 min at room temperature before the signal was read on an Envision 2104 plate reader (Perkin Elmer).

Cell thermal shift assay (CETSA)
Compounds or DMSO were incubated with 4×10 ⁶ MV411 cells for 1 hr at 37°C. Cells were placed on ice, washed with PBS, and transferred to PCR tubes. The supernatant was aspirated leaving ˜5 μl in each tube, and the proteins were denatured by heat-shocking the cells at 48.5° C. for 3 min in a thermocycler. Cells were then allowed to cool for 3 min at RT and then incubated with 35 μl lysis buffer (50 mM Tris-HCl (pH 7.5), 5% glycerol, 100 mM NaCl, 1.5 mM MgCl, 0.2% NP-40 + protease inhibitor cocktail (rested) Cells were lysed by resuspending them in )) and freezing and thawing three times using liquid nitrogen. The lysate was then clarified by spinning at 20,000 xg for 20 min to pellet aggregated proteins. The supernatant was boiled with LDS and divided into three samples for immunoblotting. Bands were quantified using Image Studio™ software and plotted as mean ± SEM of triplicates using GraphPad PRISM v6.

Xenograft experiments MV4;11 human leukemia cells (mCherry ⁺ and luciferase ⁺ ) were grown in immunodeficient (NOD.Cg-Prkdc ^scid Il2rg ^tm1Wjl /SzJ, NSG) 8-week-old female mice (2 ×10e6 cells/animal) were injected into the tail vein. Cells were tested negative for mycoplasma and rodent infectious agents at Charles River Laboratories (Mouse Comprehensive Panel). Luminescence was utilized to monitor engraftment (to ensure 7 days post-injection). At that time, MT1 at 44.2 μmol/kg (n=8), MT1 at 22.1 μmol/kg (n=9), JQ1 at 44.2 μmol/kg (n=8), Mice were randomly assigned to four cohorts that received vehicle (n=8) or 10% captisol in water, formulated in 10% DMSO solution. Mice that failed to engraft were excluded from the study. Each group was dosed once daily for 14 days (days 7-21) and bioluminescence was monitored weekly on days 7, 14, and 21 post-injection. Mice were sacrificed on day 21, bone marrow was extracted from both femurs of each mouse, and leukemic burden was determined by measuring % mcherry ⁺ cells by LSRFortessa X-20 flow cytometry (Fig. 6b ).

A second experiment was performed as above using 12-week-old mice with reliable engraftment, 17 days after injection. At that point, mice were randomized into three cohorts receiving MT1 (n=11) treatment, JQ1 (n=11) treatment, or vehicle (n=11) treatment once daily for the next 12 days. Assigned. A washout period of 2 days (days 29-30) was allowed, and treatment was resumed for an additional 5 days (days 31-35) before termination. Mice were monitored and sacrificed when hindlimb paralysis was evident or when body weight dropped by 15%. Both drugs were dosed at an equimolar concentration of 44.2 μmol/kg (50 mg/kg and 20.2 mg/kg for MT1 and JQ1, respectively).

Flow Cytometry For analysis of apoptotic cells, cells were washed with Annexin V binding buffer (140mM NaCl, 10mM HEPES, 2.5mM _CaCl2 , pH 7.4) and then 250ng/mL FITC in AnnexinV binding buffer. - Stained with Annexin V and 500 ng/mL propidium iodide. All centrifugation steps were performed at 400 xg for 5 minutes at 4°C. Flow cytometry analysis was performed on a flow cytometer (BD Biosciences) and all data were analyzed with FlowJo software (v10, Tree Star).

Immunoblotting Cells were lysed for 20 minutes on ice using RIPA buffer supplemented with protease inhibitor cocktail (Roche) and 0.1% benzonase (Novagen). Lysates were spun at 20,000 x g for 15 minutes at 4°C and protein concentration was determined by BCA assay (Pierce). The following antibodies were used in this study: BRD4 (Bethyl labs), c-MYC and actin (both Santa Cruz), HEXIM1, PARP, cleaved caspase 3 (all Cell Signaling Technology). Blots were imaged using fluorescently labeled secondary antibodies (LI-COR) on an OdysseyCLxImager (LI-COR).

Protein expression and purification
Constructs of human BRD4 covering residues 44-168 (His-BRD4(1)) or 333-460 (His-BRD4(2)) in the pNIC28Bsa4 vector (Addgene) were added to LB in the presence of 50 mg/ml kanamycin. Overexpressed in E. coli BL21 (DE3) in culture. Cells were grown at 37°C to an OD of 0.8, cooled to 17°C, induced with 500 μM isopropyl-1-thio-D-galactopyranoside, incubated overnight at 17°C, and removed by centrifugation. It was collected and stored at -80°C. For His-BRD4 (1), the cell pellet was sonicated in buffer A (50 mM HEPES (pH 7.4), 400 nM NaCl, 1 mM BME, 10 mM imidazole), and for His-BRD4 (2), the cell pellet was The pellet was sonicated in buffer B (50mM HEPES (pH 7.5), 300mM NaCl, 10% glycerol, 10mM imidazole, 3mM BME) and the resulting lysate was incubated at 30,000 x g for 30 minutes. Centrifuged for minutes. Ni-NTA beads (Qiagen) were mixed with the lysate supernatant for 30 min and washed with buffer A or B. The beads were transferred to an FPLC-compatible column and the bound proteins were dissolved in 15% Buffer C (50mM Hepes pH 7.4, 400nM NaCl, 1mM BME, 500mM Imidazole) or Buffer D (50mM HEPES (pH 7.5), 300mM NaCl, 10% glycerol, 300mM imidazole, and 3mM BME) and eluted with 100% buffer C or D. His-BRD4 (1) was dialyzed against 20mM HEPES (pH 7.5), 150mM NaCl, 1mM BME and frozen at -80°C for use in AlphaSceen™ and FP assays. For crystallographic studies of BRD4(2), TEV was added to the eluted protein and incubated overnight at 4°C. The sample was then passed through a desalting column (26/10 column) pre-equilibrated with buffer B without imidazole and the eluted protein was subjected to a second Ni-NTA step to remove the His-tag and TEV sites. was removed. The eluate was concentrated and passed through a Superdex 200 10/300 column (GE healthcare) in a buffer containing 20mM HEPES 7.5, 150mM NaCl, and 1mM DTT. Fractions were pooled, concentrated to 14 mg/ml (BD1) or 48 mg/ml (BD2), and frozen at -80°C.

Covering residues 2 to 170 (GST-BRD4(1)) in the gateway compatible pgex-6p-1 vector (Amersham) for the BRD4(1) dimerization AlphaSceen™ assay. The human BRD4 construct was overexpressed in E. coli BL21 (DE3) in LB medium in the presence of 50 mg/ml carbenicillin. Cells were grown at 37°C to an OD of 0.6, induced with 500 μM isopropyl-1-thio-D-galactopyranoside (IPTG), incubated for 4 hr at 37°C, harvested by centrifugation, and - It was stored at 80°C. The cell pellet was resuspended in buffer E (50 mM HEPES (pH 8.0), 300 mM NaCl, 10% glycerol), then lysozyme was added to a concentration of 0.33 mg/mL and the pellet was incubated for 30 min at RT. , and then sonicated. The resulting lysate was centrifuged at 30,000 xg for 30 min. The supernatant was added to 2 mL of packed Glutathione Sepharose® 4B (GE Healthcare, 17-0756-01) beads and incubated overnight at 4° C., then purified in Buffer E+16 mM glutathione in batch mode. Batches were pooled, then dialyzed against Buffer E to remove contaminating glutathione, and frozen at -80°C at a concentration of 3.23 mg/ml.

His-BRDT (1) was obtained as previously described (see, for example, Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 2010, 468, 1067-1073). An SDS page gel showing the purity of each recombinant protein can be found in Figure 20.

Crystallization, Data Collection and Structure Determination Half-equivalent MT1 (10 mM in DMSO) was mixed with 500 μM protein and ₂₀ μM in the following crystallization buffer: ₂ M NH SO and 0.1 M BisTris (pH 5.5). Crystallization was performed by sitting-drop vapor diffusion at °C. Crystals were quickly transferred into crystallization buffer containing 25% glycerol prior to flash-freezing in liquid nitrogen. Diffraction data from complex crystals were collected at NE-CAT beamline 24ID-E at the Advanced Photon Source (Argonne National Laboratory). Data sets were integrated and scaled using XDS (see, for example, Kabsch, W. Acta crystallographica. Section D, Biological crystallography 2010, 66, 133-144). The structure was solved by molecular replacement using the program Phaser (see for example McCoy, AJ et al. Phaser crystallographic software. J Appl Crystallogr 2007, 40, 658-674, doi:10.1107/S0021889807021206 ). Ligands were located and pre-refined using Buster and Rhofit (see for example Smart, OS et al. Acta Crystallogr D Biol Crystallogr 2012, 68, 368-380, doi:10.1107/S0907444911056058). Building and refining iterative manual models using Phenix and Coot has resulted in models with excellent statistics (see, for example, Adams, PD et al. Acta Crystallogr D Biol Crystallogr 2010, 66, 213-221, doi:10.1107/S0907444909052925; Emsley, P. & Cowtan, K. Acta Crystallogr D Biol Crystallogr 2004, 60, 2126-2132, doi:10.1107/S09074449040191 58). The elucidated structure was submitted to PDB as 5JWM.

Size exclusion chromatography The monomeric state of BRD4(1) in solution was determined using a Superdex 200 10/300GL column ( GE Healthcare) in a buffer containing 20mM Hepes (pH 7.5), 150mM NaCl. Protein (50 μM) and ligands (6S+2S)-PEG1 (25 μM), (6R+2R)-PEG1 (100 μM), JQ1 (100 μM) or DMSO were mixed and incubated at 20° C. for 20 min before injection. Elution peaks were monitored using ultraviolet absorption at 280 nm. BRD4(1,2) and the domain mutants BRD4(1 ^MUT , 2) and BRD4(1,2 ^MUT ) corresponding to the N140A and N433A mutants, respectively, were analyzed using the same method but with 42 μM protein. was used with the half-equivalent MT1.

Isothermal Titration Calorimetry Experiments were performed on an Auto-ITC200 titration microcalorimeter (Malvern Instruments). All experiments were performed at 25°C with stirring at 1000 rpm in ITC buffer (50mM HEPES (pH 7.4), 150mM NaCl at 25°C). A microsyringe was loaded with a solution of the ligand sample. All titrations were performed using an initial 0.4 μl injection followed by 19 identical injections of 2.0 μl with a subsequent 4 seconds (per injection) and a 120 second interval between injections. The heat of dilution was determined by independent titration (ligand into buffer) and subtracted from the experimental data. The data collected were converted into enthalpies of binding (ΔH) and binding constants (KB) as previously described by Wiseman and co-workers (see, for example, Wiseman et al. Analytical biochemistry 1989, 179, 131-137). Analyzed in MicroCal™ Origin software, which is included with the instrument for producing . Thermodynamic parameters were calculated (ΔG=ΔH−TΔS=−RTlnKB, where ΔG, ΔH, and ΔS are the change in free energy, enthalpy, and entropy of bond, respectively). In all cases, a single binding site model was adopted.

Receptor Profiling Studies Selectivity profiling (ExpresSProfile) was performed with MT1 at 1 μM for 55 ligand receptors, ion channels, and transport proteins by CEREP (Eurofins, Paris, France) using the manufacturer's protocol. did.

Statistics and Animal Model Status For all experiments, the number of replicates (n), median, error bars, and p-value cutoff are listed in the respective figure legends. Error bars are shown for all data points with reproduction as a measure of variation within each data group. All t-tests performed were Welch's t-tests allowing the estimated unequal variances and distributions to follow Student's t-distribution. These estimates are consistent with the data. All t-tests were two-sided. Statistical methods were not used to predetermine sample size. The experiment was not randomized and the investigators were not blinded to allocation during the experiment and outcome assessment. Animal experiments were performed according to protocol 13-053 approved by the Dana-Farber Cancer Institute Animal Care and Use Committee and adhered to DFCI institutional standards.

Synthesis method (6S+2S)-General procedure for the synthesis of PEG derivatives (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1 ,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (CAS #202592-23-2) (40 mg, 0.1 mmol), the corresponding mono-Boc-amino- PEG-amine (1.5eq), HATU (1.5eq), and N,N-diisopropylethylamine (1.5eq) were added to DMF (0.1M). The mixture was stirred at room temperature for 4 hours. The mixture was diluted _with EtOAc, washed with 1N NaOH and brine, dried over _Na2SO4 , filtered, and concentrated under reduced pressure. Purification of the residue by flash chromatography gave the mono-amide (49-99%). The mono-amide was dissolved in dichloromethane (0.5M). Trifluoroacetic acid (0.5M) was added to this solution. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane, washed with 1N NaOH, dried over _Na2SO4 , filtered, and concentrated under reduced pressure _. The free amine was used for the next step without purification. Free amine, (S)-4-(4-chlorophenyl)-6-(2-methoxy-2-oxoethyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4] Triazolo[4,3-a][1,4]diazepine-2-carboxylic acid (CAS #916493-82-8) (1.1eq), HATU (1.5eq), and N,N-diisopropylethylamine (1 .5eq) was added to DMF (0.1M). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate, washed with 1N NaOH and brine, dried over _Na2SO4 , filtered, and concentrated under reduced pressure _. Purification of the residue by flash chromatography gave the title compound (50-81% over two steps).

(6S+2S)-PEG0
Methyl 2-((S)-4-(4-chlorophenyl)-2-((2-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[ 3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)carbamoyl)-3,9-dimethyl-6H-thieno[3 ,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate
¹ H NMR (400 MHz, Chloroform-d)δppm 1.54 (s, 3 H) 1.97 (s, 3 H) 2.32 (s, 3 H) 2.55 (s, 6 H) 3.24 - 3.61 (m, 8 H) 3.68 (s, 3 H) 4.54 (ddd, J=9.68, 7.92, 6.26 Hz, 2 H) 7.15 - 7.25 (m, 4 H) 7.28 - 7.33 (m, 4 H) 7.73 (br. s., 1 H) 7.86 (br. s., 1 H). ¹³ C NMR (100 MHz, Chloroform-d)δppm 11.71, 11.78, 13.03, 14.30, 16.55, 36.55, 38.88, 39.18, 41.61, 51.81, 53.72, 54.17 , 128.69, 129.65 , 129.72, 130.28, 130.32, 130.78, 130.82, 131.23, 131.89, 136.18, 136.22, 136.64, 136.94, 137.20, 149.81, 150.02, 155.10, 155.44, 161.68, 163.16, 164.14, 171.62, 172.06.MS (ESI) m/z : 869 (M+H) ⁺ . HRMS (ESI) m/z: C ₄₁ H ₃₈ Cl ₂ N ₁₀ O ₄ S ₂ requires m/z 868.1896, and the found value is m/z 869.1957 (M +H) ⁺ .

(6S+2S)-PEG1
Methyl 2-((S)-4-(4-chlorophenyl)-2-((2-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H -thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethoxy)ethyl)carbamoyl)-3,9-dimethyl- 6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate
¹ H NMR (400 MHz, Chloroform-d)δppm 1.59 (s, 3 H) 2.03 (s, 3 H) 2.34 (s, 3 H) 2.50 (s, 3 H) 2.57 (s, 3 H) 3.15 (dd , J=13.69, 4.30 Hz, 1 H) 3.27 - 3.65 (m, 11 H) 3.67 (s, 3 H) 4.41 - 4.56 (m, 2 H) 7.13 - 7.25 (m, 4 H) 7.19 - 7.24 (m , 4 H) 7.52 - 7.67 (m, 2 H). ¹³ C NMR (100 MHz, Chloroform-d)δppm 11.71, 13.06, 14.30, 16.61, 36.54, 39.34, 39.61, 40.27, 51.86, 53.74, 54.6 3, 69.20, 69.43, 128.73, 128.76, 129.65, 129.73, 129.90, 130.57, 130.80, 130.91, 131.17, 131.68, 136.07, 136.22, 136.53, 136.96, 13 7.01, 137.37, 149.81, 149.91, 154.65, 155.17, 155.61, 161.84.MS (ESI) m/z: 913 (M+H) ⁺ . HRMS (ESI) m/z: C ₄₃ H ₄₂ Cl ₂ N ₁₀ O ₅ S ₂ requires m/z 912.2158, the actual value is m/z 913.2219 (M +H) ⁺ .

(6S+2S)-PEG2
Methyl 2-((S)-4-(4-chlorophenyl)-2-((2-(2-(2-(2-((S)-4-(4-chlorophenyl)-2,3,9- Trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethyl)carbamoyl)-3 ,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate
¹ H NMR (400 MHz, Chloroform-d)δppm 1.68 (m, 3 H) 2.07 (s, 3 H) 2.41 (s, 3 H) 2.56 (s, 3 H) 2.61 (s, 3 H) 3.29 - 3.74 (m, 16 H) 3.76 (s, 3 H) 4.65 (ddd, J=18.00, 8.22, 5.87 Hz, 2 H) 7.18 (br. s., 2 H) 7.28 - 7.36 (m, 4 H) 7.38 - 7.48 (m, 4 H). ¹³ C NMR (100 MHz, Chloroform-d)δppm 11.68, 13.13, 14.39, 15.26, 16.52, 36.58, 39.32, 40.12, 53.79, 54.31, 69.65, 69.80, 70 .28, 128.83, 129.75, MS (ESI) m/z: 957 (M+H) ⁺ .

(6S+2S)-PEG3
Methyl 2-((S)-4-(4-chlorophenyl)-2-((1-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2 -f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl ) carbamoyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate
¹ H NMR (400 MHz, Chloroform-d)δppm 1.60 (s, 3 H) 1.98 (s, 3 H) 2.33 (s, 3 H) 2.55 (s, 3 H) 2.57 - 2.61 (m, 3 H) 3.23 - 3.65 (m, 20 H) 3.68 - 3.75 (m, 3 H) 4.47 - 4.65 (m, 2 H) 6.94 - 7.19 (m, 2 H) 7.20 - 7.28 (m, 4 H) 7.28 - 7.40 (m, 4 H). ¹³ C NMR (100 MHz, Chloroform-d)δppm 11.70, 13.03, 14.13, 14.33, 16.44, 36.53, 38.89, 39.31, 39.95, 51.88, 53.78, 54.25, 69.34, 69. 65, 70.10, 70.39, 128.62, 128.76, 129.67, 129.77, 130.49, 130.89, 131.92, 136.29, 136.48, 136.64, 136.74, 136.98, 149.76, 149.98, 155.13, 155.66, 1 61.66, 163.18, 163.86, 170.39, 171.73. MS (ESI) m/z: 1001 ( M+H) ⁺ .

(6S+2S)-PEG4
Methyl 2-((S)-4-(4-chlorophenyl)-2-((1-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2 -f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecane-17- yl)carbamoyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate
¹ H NMR (400 MHz, chloroform-d)δppm 1.60 (br. s., 3 H) 1.98 (br. s., 3 H) 2.32 (br. s., 3 H) 2.49 - 2.57 (m, 3 H ) 2.59 (br. s., 3 H) 3.22 - 3.63 (m, 24 H) 3.69 (br. s., 3 H) 4.48 - 4.66 (m, 2 H) 5.22 (br. s., 2 H) 7.23 - 7.25 (m, 5 H) 7.32 - 7.34 (m, 4 H). ¹³ C NMR (100 MHz, Chloroform-d)δppm 11.69, 11.75, 12.99, 14.30, 16.42, 36.51, 38.78, 39.27, 39.80, 51.8 2, 53.74, 54.20, 69.37, 69.80, 69.97, 70.11, 70.31, 70.39, 128.56, 128.73, 129.63, 129.75, 130.44, 130.55, 130.78, 130.81, 1 31.93, 136.26, 136.50, 136.55, 136.62, 136.68, 136.92, 149.66, 149.95, 155.10, 155.64, 161.52, 163.14, 163.66, 170.41, 171.66. MS (ESI) m/z: 1045 (M+H) ⁺ .

(6S+2S)-PEG7
Methyl 2-((S)-4-(4-chlorophenyl)-2-((1-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2 -f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-oxo-6,9,12,15,18,21,24-heptaoxa- 3-Azahexacosan-26-yl)carbamoyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6 -yl) acetate
¹ H NMR (400 MHz, Chloroform-d)δppm 1.60 (s, 3 H) 1.99 (s, 3 H) 2.33 (s, 3 H) 2.58 (s, 3 H) 2.63 (s, 3 H) 3.26 - 3.64 (m, 28 H) 3.70 (s, 3 H) 4.50 - 4.66 (m, 2 H) 6.61 - 6.72 (m, 1 H) 6.86 (t, J=5.09 Hz, 1 H) 7.20 - 7.30 (m, 4 H) 7.31 - 7.40 (m, 4 H). ¹³ C NMR (100 MHz, Chloroform-d)δppm 11.80, 12.97, 14.29, 16.41, 36.48, 38.96, 39.33, 39.92, 51.82, 53.77, 54.24, 6 9.24, 69.69, 70.13, 70.27, 70.41, 128.55, 128.77, 129.61, 129.75, 130.34, 130.69, 130.78, 130.90, 132.05, 136.22, 136.56, 136.59, 136. 89, 137.00, 149.69, 149.96, 155.10, 155.55, 161.32, 163.05, 170.41, 171.66. MS (ESI) m/z: 1177 (M+H) ⁺ .

General procedure for the synthesis of (2S+2S)-PEG derivatives (S)-4-(4-chlorophenyl)-6-(2-methoxy-2-oxoethyl)-3,9-dimethyl-6H-thieno[3,2 -f][1,2,4]triazolo[4,3-a][1,4]diazepine-2-carboxylic acid (CAS #916493-82-8) (44mg, 0.1mmol), mono-Boc- Amino-PEG-amine (1.5eq), HATU (1.5eq), and N,N-diisopropylethylamine (1.5eq) were added to DMF (0.1M). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate, washed with 1N NaOH and brine, dried over _Na2SO4 , filtered, and concentrated under reduced pressure _. Purification of the residue by flash chromatography gave the mono-amide (93%). The mono-amide was dissolved in dichloromethane (0.5M). Trifluoroacetic acid (0.5M) was added to the solution. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane, washed with 1N NaOH, dried over _Na2SO4 , filtered, and concentrated under reduced pressure _. The free amine was used for the next step without purification. Free amine, (S)-4-(4-chlorophenyl)-6-(2-methoxy-2-oxoethyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4] Triazolo[4,3-a][1,4]diazepine-2-carboxylic acid (CAS #916493-82-8) (1.1eq), HATU (1.5eq), and N,N-diisopropylethylamine (1 .5eq) was added to DMF (0.1M). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate, washed with 1N NaOH and brine, dried over _Na2SO4 , filtered, and concentrated under reduced pressure _. Purification of the residue by flash chromatography gave the title compound (55% over two steps).

(2S+2S)-PEG1
Dimethyl 2,2'-((6S,6'S)-((oxybis(ethane-2,1-diyl))bis(azanediyl))bis(carbonyl))bis(4-(4-chlorophenyl)-3 ,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-2,6-diyl)) diacetate
¹ H NMR (400 MHz, chloroform-d)δppm 1.98 (s, 6 H) 2.59 (s, 6 H) 3.44 - 3.64 (m, 12 H) 3.68 (s, 6 H) 4.53 (t, J=6.85 Hz , 2 H) 6.54 (br. s., 2 H) 7.17 - 7.27 (m, 4 H) 7.29 - 7.40 (m, 4 H). ¹³ C NMR (100 MHz, chloroform-d)δppm 11.78, 16.49, 36.44 , 39.94, 51.88, 53.77, 69.43, 128.82, 129.58, 130.20, 131.03, 136.71, 136.83, 137.15, 149.93, 155.16, 161.53, 163.00, 171 .67. MS (ESI) m/z: 957 (M+H) ⁺ .

General procedure for the synthesis of (6S+6S)-PEG derivatives (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2 ,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetic acid (CAS #202592-23-2) (40mg, 0.1mmol), mono-Boc-amino-PEG-amine ( 1.5 eq), HATU (1.5 eq), and N,N-diisopropylethylamine (1.5 eq) were added to DMF (0.1 M). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate, washed with 1N NaOH and brine, dried over _Na2SO4 , filtered, and concentrated under reduced pressure _. Purification of the residue by flash chromatography gave the mono-amide (78-99%). The mono-amide was dissolved in dichloromethane (0.5M). Trifluoroacetic acid (0.5M) was added to the solution. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane, washed with 1N NaOH, dried over _Na2SO4 , filtered, and concentrated under reduced pressure _. The free amine was used for the next step without purification. Free amine, (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a ][1,4]Diazepin-6-yl)acetic acid (CAS #202592-23-2) (1.1 eq), HATU (1.5 eq), and N,N-diisopropylethylamine (1.5 eq) were dissolved in DMF. (0.1M). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate, washed with 1N NaOH and brine, dried over _Na2SO4 , filtered, and concentrated under reduced pressure _. Purification of the residue by flash chromatography gave the title compound (69-72% over two steps).

(6S+6S)-PEG1
Methyl 2-((S)-4-(4-chlorophenyl)-2-((2-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[ 3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)carbamoyl)-3,9-dimethyl-6H-thieno[3 ,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate
¹ H NMR (400 MHz, chloroform-d)δppm 1.66 (br. s., 6 H) 2.38 (br. s., 6 H) 2.65 (br. s., 6 H) 3.25 (d, J=10.96 Hz , 2 H) 3.49 (br. s., 2 H) 3.59 (br. s., 2 H) 3.79 (br. s., 2 H) 3.87 - 4.01 (m, 2 H) 4.10 (d, J=7.04 Hz, 2 H) 4.77 (d, J=7.04 Hz, 2 H) 7.26 (d, J=7.04 Hz, 5 H) 7.37 (d, J=7.43 Hz, 4 H) 8.49 - 8.95 (m, 2 H) ^.13C NMR (125 MHz, DMSO-d ₆ )δppm 11.73, 13.00, 14.28, 38.86, 39.58, 54.68, 68.85, 128.53, 129.86, 130.57, 130.79, 131.99, 136.49 , 136.60, 149.73, 155.75, 163.72, 170.71. MS (ESI) m/z: 869 (M+H) ⁺ .

(6S+6S)-PEG7
Methyl 2-((S)-4-(4-chlorophenyl)-2-((2-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[ 3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)carbamoyl)-3,9-dimethyl-6H-thieno[3 ,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate
¹ H NMR (500 MHz, DMSO-d ₆ )δppm 1.61 (s, 6 H) 2.40 (s, 6 H) 2.58 (s, 6 H) 3.15 - 3.30 (m, 10 H) 3.43 - 3.68 (m, 28 ¹³ C NMR (125 MHz, DMSO-d ₆ )δppm 11.31, 12.71, 14.08, 37.52, 38.65, 53.86, 69.22, 69.63, 69.78, 128.48, 129.59, 129.86, 130.18, 130.74, 132.29, 135.24, 13 6.77, 149.83, 155.14, 163.03, 169.72. MS (ESI) m/z: 1133 (M+H) ⁺ . HRMS (ESI) m/z: C ₅₄ H ₆₆ Cl ₂ N ₁₀ O ₉ S ₂ requires m/z 1132.3833, the actual value is m/z 1133.3923 (M+H) ⁺ It is.

General procedure for the synthesis of 6S+IBET derivatives I-BET151 (CAS # 1300031-49-5) (42 mg, 0.1 mmol) was dissolved in DMF (0.5 M). Sodium hydride (1.2 eq) was added to the solution. The mixture was stirred at room temperature for 30 minutes. Methyl bromoacetate (1.3 eq) was added to the mixture. The mixture was stirred at room temperature for 4 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. This methyl ester was used for the next step without purification. The methyl ester was dissolved in THF (0.5M) and methanol (0.5M). 1N NaOH (4 eq) was added to the mixture. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with 1N HCl and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. This carboxylic acid was used for the next step without purification. Carboxylic acid, corresponding mono-amide (1.5eq), HATU (1.5eq), and N,N-diisopropylethylamine (1.5eq) were added to DMF (0.1M). The mixture was stirred at room temperature for 4 hours. The mixture was diluted _with EtOAc, washed with 1N NaOH and brine, dried over _Na2SO4 , filtered, and concentrated under reduced pressure. Purification of the residue by flash chromatography gave the title compound (17-52% over 3 steps).

6S+IBET-PEG0
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1 ,4]diazepin-6-yl)-N-(2-(2-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-2-oxo-1-((R) -1-(pyridin-2-yl)ethyl)-1,2-dihydro-3H-imidazo[4,5-c]quinolin-3-yl)acetamido)ethyl)acetamide
¹ H NMR (400 MHz, Chloroform-d)δppm 1.68 (s, 3 H) 2.09 - 2.16 (m, 5 H) 2.24 - 2.33 (m, 3 H) 2.38 - 2.46 (m, 3 H) 2.61 - 2.69 ( m, 3 H) 3.17 - 3.38 (m, 4 H) 3.41 - 3.71 (m, 6 H) 4.64 (dd, J=9.39, 5.48 Hz, 1 H) 4.83 - 5.01 (m, 2 H) 6.41 (d, J=7.04 Hz, 1 H) 7.12 - 7.21 (m, 1 H) 7.29 - 7.35 (m, 2 H) 7.36 - 7.44 (m, 2 H) 7.48 - 7.63 (m, 2 H) 7.84 (s, 1 H ) 7.92 (br. s., 1 H) 8.61 (d, J=4.70 Hz, 1 H) 8.78 (s, 1 H). ¹³ C NMR (100 MHz, chloroform-d)δppm 10.7, 11.7, 11.8, 13.1 , 14.4, 38.8, 39.1, 39.6, 54.5, 55.7, 76.7, 77.0, 77.3, 112.3, 115.8, 121.6, 122.7, 123.7, 128.8, 129.8, 130.4, 130.9, 13 1.1, 132.1, 136.4, 137.0, 137.3, 149.3, 150.0 , 155.5, 155.9, 159.6, 164.2, 166.4, 166.8, 171.4. MS (ESI) m/z: 898 (M+H) ⁺ .

6S+IBET-PEG1
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1 ,4]diazepin-6-yl)-N-(2-(2-(2-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-2-oxo-1-( (R)-1-(pyridin-2-yl)ethyl)-1,2-dihydro-3H-imidazo[4,5-c]quinolin-3-yl)acetamide)ethoxy)ethyl)acetamide
¹ H NMR (400 MHz, Chloroform-d)δppm 1.66 (s, 3 H) 2.05 (s, 3 H) 2.16 (s, 3 H) 2.32 (s, 3 H) 2.42 (s, 3 H) 2.72 (s , 3 H) 3.11 - 3.28 (m, 4 H) 3.43 - 3.60 (m, 6 H) 3.61 - 3.71 (m, 2 H) 3.74 - 3.84 (m, 1 H) 3.86 - 3.97 (m, 1 H) 4.69 (dd, J=11.35, 3.91 Hz, 1 H) 4.96 (s, 2 H) 6.42 (d, J=7.43 Hz, 1 H) 6.62 - 6.94 (m, 1 H) 7.21 (dd, J=7.24, 4.89 Hz, 1 H) 7.28 - 7.42 (m, 4 H) 7.59 (td, J=7.63, 1.57 Hz, 1 H) 7.86 (s, 1 H) 8.55 (br. s., 1 H) 8.63 (d, J =4.30 Hz, 1 H) 8.86 (br. s., 1 H) 9.19 (s, 1 H). ¹³ C NMR (100 MHz, Chloroform-d)δppm 10.8, 11.7, 11.9, 13.1, 14.3, 39.2, 39.6 , 39.9, 44.9, 54.9, 55.8, 55.8, 69.1, 69.2, 112.4, 115.9, 121.7, 122.6, 128.8, 129.8, 130.5, 131.0, 131.1, 131.9, 136.6, 136.8, 137.3, 149.2, 149.8, 155.7, 159.6, 164.2 , 166.3, 167.0, 170.7. MS (ESI) m/z: 942 (M+H) ⁺ .

6S+IBET-PEG2
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1 ,4]diazepin-6-yl)-N-(2-(2-(2-(2-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-2-oxo- 1-((R)-1-(pyridin-2-yl)ethyl)-1,2-dihydro-3H-imidazo[4,5-c]quinolin-3-yl)acetamido)ethoxy)ethoxy)ethyl)acetamide
¹ H NMR (400 MHz, chloroform-d)δppm 1.18 (br. s., 2 H) 1.59 (br. s., 3 H) 1.97 (br. s., 1 H) 2.01 - 2.15 (m, 4 H ) 2.22 (br. s., 3 H) 2.33 (br. s., 3 H) 2.61 (br. s., 3 H) 3.16 - 3.74 (m, 10 H) 3.96 - 4.13 (m, 1 H) 4.64 (br. s., 1 H) 4.70 - 4.87 (m, 2 H) 6.36 (br. s., 1 H) 6.76 (br. s., 1 H) 7.08 - 7.41 (m, 5 H) 7.52 (br MS (ESI) m/z: 986 (M+H) ⁺ .

6S+IBET-PEG3
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1 ,4]diazepin-6-yl)-N-(1-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-2-oxo-1-((R)-1- (pyridin-2-yl)ethyl)-1,2-dihydro-3H-imidazo[4,5-c]quinolin-3-yl)-2-oxo-6,9,12-trioxa-3-azatetradecane- 14-yl)acetamide
¹ H NMR (400 MHz, Chloroform-d)δppm 1.66 (s, 3 H) 2.12 (s, 3 H) 2.14 (s, 3 H) 2.29 (s, 3 H) 2.41 (s, 3 H) 2.61 - 2.73 (m, 3 H) 3.28 - 3.47 (m, 4 H) 3.48 - 3.57 (m, 3 H) 3.59 - 3.72 (m, 11 H) 3.74 - 3.83 (m, 2 H) 4.66 - 4.84 (m, 3 H) ) 6.40 (br. s., 1 H) 6.79 (br. s., 1 H) 7.13 - 7.24 (m, 2 H) 7.29 - 7.45 (m, 3 H) 7.53 - 7.65 (m, 1 H) 7.78 ( s, 1 H) 8.08 (br. s., 1 H) 8.37 - 8.49 (m, 1 H) 8.54 (br. s., 1 H) 8.64 (d, J=4.30 Hz, 1 H), ¹³ C NMR (100 MHz, Chloroform-d)δppm 10.73, 11.65, 11.83, 13.08, 14.37, 29.67, 38.68, 39.27, 39.33, 54.44, 55.7, 69.69, 69.88, 70.05, 70.19, 1 12.5, 115.9, 121.63, 122.6, 128.53, 129.76 , 130.73, 130.95, 131.0, 131.3, 131.85, 133.07, 136.23, 136.69, 137.33, 149.15, 150.04, 154.58, 155.28, 156.12, 159.68, 1 63.97, 166.27, 166.73, 170.74. Exact mass: 1029.3723. MS (ESI) m/z: 1030 (M+H) ⁺ .

6S+IBET-PEG4 (MT_5_112_1)
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1 ,4]diazepin-6-yl)-N-(1-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-2-oxo-1-((R)-1- (pyridin-2-yl)ethyl)-1,2-dihydro-3H-imidazo[4,5-c]quinolin-3-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecane -17-yl)acetamide
¹ H NMR (400 MHz, chloroform-d)δppm 1.55 (s, 3 H) 1.93 (s, 3 H) 1.99 - 2.07 (m, 3 H) 2.12 - 2.21 (m, 3 H) 2.28 (s, 3 H) ) 2.35 - 2.49 (m, 2 H) 2.52 - 2.60 (m, 3 H) 3.30 - 3.45 (m, 8 H) 3.46 - 3.64 (m, 15 H) 4.60 (t, J=6.85 Hz, 1 H) 4.74 (s, 2 H) 6.32 (d, J=6.65 Hz, 1 H) 7.05 - 7.13 (m, 1 H) 7.14 - 7.24 (m, 2 H) 7.29 (d, J=8.61 Hz, 2 H) 7.48 ( t, J=7.04 Hz, 1 H) 7.57 (br. s., 1 H) 7.69 (s, 1 H) 7.80 (br. s., 1 H) 8.52 (d, J=4.30 Hz, 1 H) 8.58 (s, 1 H). ¹³ C NMR (100 MHz, chloroform-d)δppm 14.38, 121.61, 130.62, 136.58, 136.65, 166.57, 170.56, 223.24, 223.78. MS (ESI) m/z: 1074 (M+H ) ⁺ .

6S+IBET-PEG7 (MT_5_102_1)
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1 ,4]diazepin-6-yl)-N-(1-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-2-oxo-1-((R)-1- (pyridin-2-yl)ethyl)-1,2-dihydro-3H-imidazo[4,5-c]quinolin-3-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecane -17-yl)acetamide
¹ H NMR (400 MHz, Chloroform-d)δppm 1.56 (s, 3 H) 2.00 - 2.09 (m, 5 H) 2.18 (s, 3 H) 2.29 (s, 3 H) 2.55 (s, 3 H) 3.28 (dd, J=14.67, 7.24 Hz, 1 H) 3.35 - 3.45 (m, 5 H) 3.47 - 3.63 (m, 32 H) 4.56 (t, J=7.04 Hz, 1 H) 4.67 - 4.83 (m, 2 H) 6.33 (d, J=7.43 Hz, 1 H) 7.12 (dd, J=7.24, 4.89 Hz, 1 H) 7.15 - 7.26 (m, 3 H) 7.30 (d, J=8.61 Hz, 2 H) 7.51 (t, J=7.04 Hz, 1 H) 7.70 (s, 2 H) 8.54 (d, J=4.70 Hz, 1 H) 8.58 (s, 1 H). ¹³ C NMR (100 MHz, chloroform-d)δppm 10.64, 10.71, 11.55, 11.64, 11.69, 11.79, 12.96, 13.05, 14.32, 38.88, 39.30, 39.47, 54.25, 54.34, 70.15, 70.21, 70.36, 11 2.40, 115.84, 121.63, 122.65, 123.67, 128.15, 128.59, 129.77, 129.83, 130.41, 130.73, 130.82, 131.31, 131.37, 132.06, 133.09, 133.20, 136.59, 136.64, 140.93, 149.18, 149.24, 149.74, 1 54.55, 155.30, 155.65, 159.60, 163.70, 166.23, 166.48, 170.54.MS (ESI) m/z: 1206 (M+H) ⁺ .

General procedure for the synthesis of 6S+IBET derivatives I-BET151 (CAS # 1300031-49-5) (42 mg, 0.1 mmol) was dissolved in DMF (0.5 M). Sodium hydride (1.2 eq) was added to this solution. The mixture was stirred at room temperature for 30 minutes. Methyl bromoacetate (1.3 eq) was added to the mixture. The mixture was stirred at room temperature for 4 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. This methyl ester was used for the next step without purification. The methyl ester was dissolved in THF (0.5M) and methanol (0.5M). 1N NaOH (4 eq) was added to the mixture. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with 1N HCl and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The carboxylic acid was used for the next step without purification. Carboxylic acid, corresponding mono-Boc-amino-PEG-amine (1.5eq), HATU (1.5eq), and N,N-diisopropylethylamine (1.5eq) were added to DMF (0.1M). . The mixture was stirred at room temperature for 4 hours. The mixture was diluted _with EtOAc, washed with 1N NaOH and brine, dried over _Na2SO4 , filtered, and concentrated under reduced pressure. Purification of the residue by flash chromatography gave the mono-amide (54-88% over 3 steps). The mono-amide was dissolved in dichloromethane (0.5M). Trifluoroacetic acid (0.5M) was added to this solution. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane, washed with 1N NaOH, dried over _Na2SO4 , filtered, and concentrated under reduced pressure _. This amine was used for the next step without purification. The amine, (S)-4-(4-chlorophenyl)-6-(2-methoxy-2-oxoethyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4] Triazolo[4,3-a][1,4]diazepine-2-carboxylic acid (CAS #916493-82-8) (1.1eq), HATU (1.5eq), and N,N-diisopropylethylamine (1 .5eq) was added to DMF (0.1M). The mixture was stirred at room temperature for 4 hours. The mixture was diluted _with EtOAc, washed with 1N NaOH and brine, dried over _Na2SO4 , filtered, and concentrated under reduced pressure. Purification of the residue by flash chromatography gave the title compound (38-64% over two steps).

2S+IBET-PEG0
Methyl 2-((S)-4-(4-chlorophenyl)-2-((2-(2-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-2-oxo -1-((R)-1-(pyridin-2-yl)ethyl)-1,2-dihydro-3H-imidazo[4,5-c]quinolin-3-yl)acetamido)ethyl)carbamoyl)-3 ,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate
¹ H NMR (400 MHz, methanol-d4)δppm 1.90 (s, 3 H) 1.94 (s, 3 H) 2.07 - 2.14 (m, 5 H) 2.61 (s, 3 H) 3.08 (s, 3 H) 3.27 (dt, J=3.23, 1.71 Hz, 2 H) 3.44 - 3.46 (m, 2 H) 3.69 (s, 3 H) 3.72 (s, 1 H) 4.60 (t, J=7.24 Hz, 1 H) 4.77 - 4.82 (m, 3 H) 4.86 (d, J=4.70 Hz, 2 H) 6.33 (d, J=7.43 Hz, 1 H) 6.73 (br. s., 1 H) 7.12 - 7.18 (m, 2 H) 7.20 - 7.26 (m, 2 H) 7.29 (dd, J=7.43, 5.09 Hz, 1 H) 7.34 - 7.40 (m, 1 H) 7.43 (s, 2 H) 7.45 - 7.49 (m, 1 H) 7.72 ( td, J=7.83, 1.57 Hz, 1 H) 8.53 (d, J=4.30 Hz, 1 H) 8.59 (s, 1 H). ¹³ C NMR (100 MHz, methanol-d4)δppm 10.76, 11.63, 11.76, 11.87, 15.79, 16.92, 18.52, 37.33, 40.56, 41.45, 45.14, 52.58, 54.99, 56.7, 113.61, 117.38, 122.78, 123.2, 124.46, 125.48 , 129.81, 129.96, 130.06, 130.3, 131.29, 131.44, 131.62, 132.42, 132.58, 133.47, 135.5, 137.66, 138.11, 138.59, 139.35, 141.84, 150.73, 152.62, 156.18, 156.81, 156.95, 160.91, 164.29, 16 5.34, 168.09, 169.91, 173.1, 173.21. MS (ESI) m/z: 942 ( M+H) ⁺ _.

2S+IBET-PEG1
Methyl 2-((S)-4-(4-chlorophenyl)-2-((2-(2-(2-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy- 2-oxo-1-((R)-1-(pyridin-2-yl)ethyl)-1,2-dihydro-3H-imidazo[4,5-c]quinolin-3-yl)acetamido)ethoxy)ethyl ) carbamoyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate
¹ H NMR (400 MHz, methanol-d4)δppm 1.94 (s, 3 H) 2.00 (s, 3 H) 2.04 - 2.08 (m, 3 H) 2.18 (s, 3 H) 2.61 (s, 3 H) 3.04 (s, 2 H) 3.24 (dt, J=3.13, 1.57 Hz, 2 H) 3.35 - 3.62 (m, 6 H) 3.63 (s, 3 H) 3.69 (s, 1 H) 3.96 - 4.06 (m, 1 H) 4.76 - 4.78 (m, 5 H) 6.30 (q, J=7.30 Hz, 1 H) 6.75 (br. s., 1 H) 7.21 - 7.30 (m, 3 H) 7.31 - 7.37 (m, 3 H) ) 7.38 - 7.47 (m, 2 H) 7.63 - 7.66 (m, 1 H) 7.70 (td, J=7.73, 1.76 Hz, 1 H) 8.50 (d, J=4.30 Hz, 1 H) 8.59 (s, 1 H). ¹³ C NMR (100 MHz, methanol-d4)δppm 10.77, 11.65, 11.74, 11.83, 14.61, 15.78, 16.81, 18.36, 37.27, 40.85, 41.26, 52.54, 52.56, 55.0 4, 56.73, 70.41, 70.49, 113.74 , 122.76, 123.41, 124.46, 125.50, 129.96, 130.07, 131.38, 131.44, 132.54, 132.59, 133.49, 135.53, 137.93, 138.25, 138.28, 138.35, 138.37, 139.35, 141.75, 150.75, 152.61, 156.93, 157.06, 161.00, 164.09 , 165.62, 165.75, 168.20, 169.36, 173.14. MS (ESI) m/z: 986 (M+H) ⁺ .

2S+IBET-PEG2
Methyl 2-((S)-4-(4-chlorophenyl)-2-((2-(2-(2-(2-(7-(3,5-dimethylisoxazol-4-yl)-8 -methoxy-2-oxo-1-((R)-1-(pyridin-2-yl)ethyl)-1,2-dihydro-3H-imidazo[4,5-c]quinolin-3-yl)acetamide) ethoxy)ethoxy)ethyl)carbamoyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl ) acetate
¹ H NMR (400 MHz, chloroform-d)δppm 1.94 (d, J=8.22 Hz, 3 H) 2.01 (s, 3 H) 2.09 (m, 2 H) 2.117 (s, 3 H) 2.55 (s, 3 H) 3.25 - 3.55 (m, 18 H) 3.64 (s, 3 H) 4.53 (dd, J=7.83, 6.26 Hz, 1 H) 4.58 - 4.73 (m, 2 H) 6.29 (q, J=6.78 Hz, 1 H) 6.53 - 6.77 (m, 1 H) 6.85 (br. s., 1 H) 6.93 (br. s., 1 H) 7.09 - 7.16 (m, 2 H) 7.17 - 7.22 (m, 2 H) 7.23 - 7.32 (m, 2 H) 7.54 (td, J=7.63, 1.57 Hz, 1 H) 7.69 (s, 1 H) 8.49 (d, J=4.70 Hz, 1 H) 8.56 (s, 1 H). ¹³ C NMR (100 MHz, Chloroform-d)δppm 10.68, 10.76, 11.60, 11.77, 16.49, 36.53, 45.04, 52.02, 53.90, 69.45, 70.09, 112.28, 115.83, 122.16 , 123.26, 128.80, 128.91, 129.64, 131.03, 133.09, 133.20, 136.25, 136.71, 136.94, 137.11, 141.07, 149.41, 150.03, 154.44, 155.21, 155.56, 159.54, 161.64, 163.13, 1 66.34, 168.45, 171.88. MS (ESI) m/z: 1030 (M+H) ⁺ .

2S+IBET-PEG3
Methyl 2-((S)-4-(4-chlorophenyl)-2-((1-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-2-oxo-1- ((R)-1-(pyridin-2-yl)ethyl)-1,2-dihydro-3H-imidazo[4,5-c]quinolin-3-yl)-2-oxo-6,9,12- trioxa-3-azatetradecan-14-yl)carbamoyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4] diazepin-6-yl)acetate
¹ H NMR (400 MHz, chloroform-d)δppm 1.98 (d, J=8.22 Hz, 3 H) 2.02 - 2.11 (m, 5 H) 2.21 (s, 3 H) 2.38 (br. s., 2 H) 2.55 - 2.66 (m, 3 H) 3.04 (s, 2 H) 3.32 - 3.65 (m, 16 H) 3.66 - 3.76 (m, 3 H) 4.49 - 4.63 (m, 1 H) 4.65 - 4.82 (m, 2 H) 6.32 (d, J=7.04 Hz, 1 H) 6.71 (br. s., 1 H) 7.04 (br. s., 1 H) 7.12 - 7.40 (m, 6 H) 7.56 (t, J=7.43 ¹³ C NMR (100 MHz, chloroform-d)δppm 10.64, 10.72, 11.65, 11.82, 14.10, 15.62, 16.53, 36.50, 39.43, 40.04, 44.69, 51.84, 51.98, 53.74, 53.83, 69.52, 69.93, 70.04, 70.20, 70.31, 11 2.29, 115.83, 121.96, 122.70, 122.80, 123.43, 128.79, 129.68, 130.46, 130.94, 131.13, 131.21, 133.09, 133.20, 136.21, 136.72, 136.84, 137.03, 140.98, 149.32, 149.38, 150.01, 152.18, 1 55.17, 155.46, 159.53, 161.58, 163.11, 166.35, 171.81. MS (ESI) m/ z: 1074 (M+H) ⁺ .

2S+IBET-PEG4
Methyl 2-((S)-4-(4-chlorophenyl)-2-((1-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-2-oxo-1- ((R)-1-(pyridin-2-yl)ethyl)-1,2-dihydro-3H-imidazo[4,5-c]quinolin-3-yl)-2-oxo-6,9,12, 15-Tetraoxa-3-azaheptadecan-17-yl)carbamoyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4 ]Diazepin-6-yl)acetate
¹ H NMR (400 MHz, Chloroform-d)δppm 1.93 (s, 3 H) 1.96 (s, 3 H) 2.00 - 2.06 (m, 3 H) 2.17 (s, 3 H) 2.21 - 2.35 (m, 2 H ) 2.56 (s, 3 H) 3.26 - 3.61 (m, 23 H) 3.62 - 3.69 (m, 3 H) 4.47 - 4.56 (m, 1 H) 4.64 - 4.83 (m, 2 H) 6.28 (d, J= 7.04 Hz, 1 H) 6.69 (br. s., 1 H) 7.04 - 7.24 (m, 5 H) 7.29 (d, J=8.22 Hz, 2 H) 7.51 (t, J=7.04 Hz, 2 H) 7.64 - 7.75 (m, 1 H) 8.51 (d, J=4.30 Hz, 1 H) 8.55 (s, 1 H). ¹³ C NMR (100 MHz, chloroform-d)δppm 16.51, 16.58, 36.54, 53.77, 53.84, 70.13, 70.28, 112.34, 115.87, 121.91, 123.57, 128.81, 129.73, 130.37, 130.96, 136.24, 136.76, 136.99, 137.06, 140.97, 149 .30, 149.37, 150.07, 153.90, 155.21, 155.45, 159.57, 161.70, 163.18, 166.30, 166.51, 171.81. MS (ESI) m/z: 1118 (M+H) ⁺ .

2S+IBET-PEG7
Methyl 2-((S)-4-(4-chlorophenyl)-2-((1-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-2-oxo-1- ((R)-1-(pyridin-2-yl)ethyl)-1,2-dihydro-3H-imidazo[4,5-c]quinolin-3-yl)-2-oxo-6,9,12, 15,18,21,24-heptaoxa-3-azahexacosan-26-yl)carbamoyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3- a][1,4]diazepin-6-yl)acetate
¹ H NMR (400 MHz, chloroform-d)δppm 1.93 (s, 3 H) 1.95 (s, 3 H) 2.04 (d, J=7.43 Hz, 2 H) 2.17 (s, 3 H) 2.49 (br. s ., 2 H) 2.58 (s, 3 H) 3.31 - 3.60 (m, 36 H) 3.62 - 3.71 (m, 3 H) 4.52 (dd, J=7.83, 6.26 Hz, 1 H) 4.66 - 4.82 (m, 2 H) 6.32 (d, J=7.04 Hz, 1 H) 6.49 - 6.85 (m, 2 H) 7.04 (br. s., 1 H) 7.12 (dd, J=7.04, 5.09 Hz, 1 H) 7.16 - 7.25 (m, 2 H) 7.26 - 7.33 (m, 2 H) 7.46 - 7.60 (m, 2 H) 7.68 (s, 1 H) 8.53 (d, J=4.70 Hz, 1 H) 8.57 (s, 1 H ). ¹³ C NMR (100 MHz, Chloroform-d)δppm 36.52, 39.53, 39.99, 44.46, 53.84, 55.60, 59.38, 70.26, 112.36, 115.83, 121.77, 123.65, 128.76, 1 29.69, 130.63, 130.92, 136.25, 136.64, 136.84, 137.01, 140.91, 155.16, 155.36, 159.56, 161.48, 163.14, 166.26, 166.42. MS (ESI) m/z: 1250 (M+H) ⁺ .

General procedure for the synthesis of IBETx2 derivatives I-BET151 (CAS# 1300031-49-5) (42 mg, 0.1 mmol) was dissolved in DMF (0.5 M). Sodium hydride (1.2 eq) was added to this solution. The mixture was stirred at room temperature for 30 minutes. Methyl bromoacetate (1.3 eq) was added to the mixture. The mixture was stirred at room temperature for 4 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. This methyl ester was used for the next step without purification. The methyl ester was dissolved in THF (0.5M) and methanol (0.5M). 1N NaOH (4 eq) was added to the mixture. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with 1N HCl and brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. This carboxylic acid was used for the next step without purification. The carboxylic acid, the corresponding mono-Boc-amino-PEG-amine (1.5 eq), HATU (1.5 eq), and N,N-diisopropylethylamine (1.5 eq) were added to DMF (0.1 M). Ta. The mixture was stirred at room temperature for 4 hours. The mixture was diluted _with EtOAc, washed with 1N NaOH and brine, dried over _Na2SO4 , filtered, and concentrated under reduced pressure. Purification of the residue by flash chromatography gave the mono-amide (54-88% over 3 steps). The mono-amide was dissolved in dichloromethane (0.5M). Trifluoroacetic acid (0.5M) was added to this solution. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane, washed with 1N NaOH, dried over _Na2SO4 , filtered, and concentrated under reduced pressure _. This amine was used for the next step without purification. The amine, the carboxylic acid (1.1 eq), HATU (1.5 eq), and N,N-diisopropylethylamine (1.5 eq) were added to DMF (0.1 M). The mixture was stirred at room temperature for 4 hours. The mixture was diluted _with EtOAc, washed with 1N NaOH and brine, dried over _Na2SO4 , filtered, and concentrated under reduced pressure. Purification of the residue by flash chromatography gave the title compound (26-45% over two steps).

IBETx2-PEG0
N,N'-(ethane-1,2-diyl)bis(2-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-2-oxo-1-((R) -1-(pyridin-2-yl)ethyl)-1,2-dihydro-3H-imidazo[4,5-c]quinolin-3-yl)acetamide)
¹ H NMR (400 MHz, chloroform-d)δppm 2.07 - 2.19 (m, 12 H) 2.24 - 2.29 (m, 6 H) 3.48 (d, J=17.22 Hz, 10 H) 4.62 - 4.86 (m, 4 H) ) 6.42 (q, J=6.65 Hz, 2 H) 6.66 - 6.92 (m, 2 H) 7.22 (dd, J=7.24, 4.89 Hz, 2 H) 7.35 - 7.50 (m, 4 H) 7.63 (td, J ¹³ C NMR (100 MHz, chloroform-d)δppm 112.30, 115.87 , 122.14, 137.38, 141.13, 149.32, 153.82, 155.58, 159.57, 166.34, 167.65, 223.24. Exact mass: 970.3875. MS (ESI) m/z: 971 (M+H) ⁺ .

IBETx2-PEG1
N,N'-(oxybis(ethane-2,1-diyl))bis(2-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-2-oxo-1-( (R)-1-(pyridin-2-yl)ethyl)-1,2-dihydro-3H-imidazo[4,5-c]quinolin-3-yl)acetamide)
¹ H NMR (400 MHz, chloroform-d)δppm 2.07 - 2.19 (m, 12 H) 2.30 (s, 6 H) 3.44 - 3.65 (m, 14 H) 4.79 (q, J=16.04 Hz, 4 H) 6.42 (d, J=7.04 Hz, 2 H) 6.63 - 6.98 (m, 2 H) 7.23 (dd, J=7.43, 4.70 Hz, 2 H) 7.35 (br. s., 2 H) 7.62 (td, J= ¹³ C NMR (100 MHz, Chloroform-d)δppm 10.69, 10.76, 11.62, 11.71, 17.74, 39.71, 45.04, 55.71, 55.78, 69.21, 112.27, 115.92, 121.26, 122.27, 122.77, 123.43, 128.48, 131.07, 131.15, 132.93 Exact mass: 1014.4137. MS (ESI) m/z: 1015 (M+H) ⁺ .

IBETx2-PEG2
N,N'-((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(2-(7-(3,5-dimethylisoxazol-4-yl) -8-Methoxy-2-oxo-1-((R)-1-(pyridin-2-yl)ethyl)-1,2-dihydro-3H-imidazo[4,5-c]quinolin-3-yl) acetamide)
¹ H NMR (400 MHz, chloroform-d)δppm 1.97 (s, 6 H) 2.21 (br. s, 10 H) 2.47 (br. s., 4 H) 3.41 (d, J=17.22 Hz, 10 H) 3.48 - 3.58 (m, 6 H) 4.62 - 4.85 (m, 4 H) 6.36 (d, J=7.04 Hz, 2 H) 6.52 - 6.89 (m, 2 H) 7.09 - 7.18 (m, 2 H) 7.31 ( br. s., 2 H) 7.44 - 7.64 (m, 4 H) 7.74 (s, 2 H) 8.53 (d, J=4.70 Hz, 2 H) 8.62 (s, 2 H). ¹³ C NMR (100 MHz , Chloroform-d)δppm 10.67, 10.75, 11.59, 11.69, 39.54, 55.75, 69.49, 70.11, 101.03, 112.32, 115.86, 121.27, 121.35, 122.04, 122.74 , 122.85, 123.43, 128.32, 131.16, 131.24, 133.09, 133.21, 137.38, 137.49, 141.04, 149.29, 154.51, 155.51, 159.38, 159.57, 166.33, 166.62. Exact mass: 1058.4399. MS (ESI) m/z: 1059 (M+H) ⁺ .
IBETx2-PEG3
N,N'-(((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(2-(7-(3,5-dimethylisoxa) sol-4-yl)-8-methoxy-2-oxo-1-((R)-1-(pyridin-2-yl)ethyl)-1,2-dihydro-3H-imidazo[4,5-c] quinolin-3-yl)acetamide)
¹ H NMR (400 MHz, chloroform-d)δppm 2.09 - 2.21 (m, 12 H) 2.28 (s, 6 H) 2.58 (br. s., 4 H) 3.36 - 3.56 (m, 8 H) 3.58 - 3.73 (m, 10 H) 4.69 - 4.96 (m, 4 H) 6.41 (d, J=7.04 Hz, 2 H) 6.62 - 6.96 (m, 2 H) 7.21 (dd, J=7.43, 5.09 Hz, 2 H) 7.35 (br. s., 2 H) 7.51 - 7.71 (m, 4 H) 7.80 (s, 2 H) 8.61 (d, J=4.30 Hz, 2 H) 8.68 (s, 2 H). ¹³ C NMR ( 100 MHz, Chloroform-d)δppm 10.66, 10.73, 11.57, 11.66, 14.12, 39.58, 44.58, 55.71, 60.33, 69.61, 69.96, 70.17, 101.05, 112.34, 115.8 5, 121.28, 121.38, 121.86, 122.64, 122.74, 123.56, Accurate Mass: 1102.4661. MS (ESI) m/z: 1103 (M+H) ⁺ .

IBETx2-PEG4
N,N'-(3,6,9,12-tetraoxatetradecane-1,14-diyl)bis(2-(7-(3,5-dimethylisoxazol-4-yl)-8-methoxy -2-oxo-1-((R)-1-(pyridin-2-yl)ethyl)-1,2-dihydro-3H-imidazo[4,5-c]quinolin-3-yl)acetamide)
¹ H NMR (400 MHz, chloroform-d)δppm 2.08 - 2.20 (m, 6 H) 2.28 (s, 6 H) 2.53 (br. s., 4 H) 3.52 (d, J=3.52 Hz, 4 H) 3.63 (t, J=4.89 Hz, 4 H) 3.66 - 3.75 (m, 10 H) 4.74 - 4.99 (m, 4 H) 6.43 (d, J=7.04 Hz, 2 H) 6.63 - 7.02 (m, 2 H) ) 7.15 - 7.25 (m, 2 H) 7.34 (br. s., 2 H) 7.60 (t, J=7.24 Hz, 2 H) 7.72 - 7.87 (m, 4 H) 8.62 (d, J=4.70 Hz, 2 H) 8.68 (s, 2 H). ¹³ C NMR (100 MHz, Chloroform-d)δppm 10.66, 10.73, 11.58, 11.66, 14.13, 17.66, 39.62, 44.41, 55.61, 55.70, 69.76, 70.14 , 70.35, 101.12 , 112.38, 115.89, 121.47, 121.79, 122.61, 122.71, 123.67, 128.24, 131.28, 131.36, 133.11, 133.23, 137.29, 137.38, 140.98, 149.25, 154.64, 155.40, 159.60, 166.28, 166.56. Exact mass: 1146.4923. MS (ESI) m/z: 1147 (M+H) ⁺ .

IBETx2-PEG7
N,N'-(3,6,9,12,15,18,21-heptaoxatricosane-1,23-diyl)bis(2-(7-(3,5-dimethylisoxazole-4- yl)-8-methoxy-2-oxo-1-((R)-1-(pyridin-2-yl)ethyl)-1,2-dihydro-3H-imidazo[4,5-c]quinoline-3- acetamide)
¹ H NMR (400 MHz, chloroform-d)δppm 2.08 - 2.20 (m, 12 H) 2.27 (s, 6 H) 3.40 - 3.73 (m, 34 H) 4.74 - 4.94 (m, 4 H) 6.43 (d, J=6.65 Hz, 2 H) 6.62 - 6.99 (m, 2 H) 7.21 (dd, J=7.04, 5.09 Hz, 2 H) 7.32 (br. s., 2 H) 7.54 - 7.65 (m, 4 H) 7.79 (s, 2 H) 8.63 (d, J=4.69 Hz, 2 H) 8.66 (s, 2 H). ¹³ C NMR (100 MHz, chloroform-d)δppm 10.64, 10.72, 11.55, 11.66, 39.57, 44.43 , 55.60, 55.71, 69.61, 70.26, 70.36, 101.12, 112.38, 115.84, 121.37, 121.47, 121.73, 122.57, 122.69, 123.63, 128.19, 131. 27, 131.35, 133.09, 133.20, 137.22, 137.32, 140.95, 149.20, 149.28, 154.55 , 155.36, 159.59, 166.25, 166.48. Exact mass: 1278.5710. MS (ESI) m/z: 1279 (M+H) ⁺ .

Equivalents and Scope In the claims, articles such as "a,""an," and "the" may mean one or more than one, unless there is an indication to the contrary or otherwise. Unless it is clear from the context. A claim or statement that includes an "or" between one or more members of a group indicates that one, more than one, or all of the members of the group are present in a given product or process. is considered to satisfy, be used for, or otherwise relate to, unless there is an indication to the contrary or otherwise is not clear from the context. The invention encompasses embodiments in which exactly one member of the group is present in, used in, or otherwise relates to a given product or process. The invention encompasses embodiments in which more than one or all of the members of the group are present in, used in, or otherwise relate to a given product or process. .

Moreover, the invention covers all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, one claim may be dependent on another claim and modified to include one or more limitations found in any other claim that is dependent on the same base claim. When elements are displayed as enumerated, eg, in Markush group format, each subgroup of the elements is also disclosed, and any element(s) may be removed from the group. Generally, when the invention, or an aspect of the invention, is viewed as including particular elements and/or features, an aspect of the invention or an aspect of the invention consists of or consists of such elements and/or features. It should be understood to consist essentially of: For purposes of brevity, those aspects are not specifically set forth herein in haec verba. It is also noted that the terms "comprising" and "containing" are intended to be open, allowing the inclusion of additional elements or steps. When a range is given, endpoints are also included. Moreover, unless indicated otherwise or is otherwise clear from the context and understanding of those skilled in the art, values expressed as ranges refer to either specific numerical values or different values of the present invention. Subranges within the ranges stated in the embodiments may be envisioned, up to ten times the units at the lower end of the range, unless the context clearly dictates otherwise.

This application references various issued patents, published patent applications, scholarly articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any incorporated references and the present specification, the present specification will control. Additionally, any particular aspect of the invention that falls within the scope of the prior art may be expressly excluded from any one or more of the claims. Because such aspects are considered known to those skilled in the art, they may be excluded even if such exclusion is not expressly specified herein. Any particular aspect of the invention may be excluded from any claim for any reason, whether or not with respect to the existence of prior art.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above description, but rather is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the invention, as defined in the following claims.

Claims (47)

Formula (Ic):
A compound represented by, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in which:
R ¹ , R ² , R ³ , and R ⁴ in any case are independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted C _1-6 alkyl, optionally substituted C _1-6 is acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ;
Each occurrence of R ^a is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or an oxygen protecting group;
Each occurrence of R ^b is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or a nitrogen protecting group;
In each case R ^c is independently hydrogen, optionally substituted C _1-6 alkyl, or optionally substituted C _1-6 acyl;
R ⁵ is hydrogen, optionally substituted C _1-6 alkyl, -OR ^5a , or -N(R ^5b ) ₂ ;
In any case, R ^5a is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or an oxygen protecting group;
In any case, R ^5b is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, optionally substituted -C _1-6 alkyl-heterocyclyl, or a nitrogen protecting group;
m in each case is independently 0, 1, 2, 3, 4, or 5;
Each R ^N is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or a nitrogen protecting group;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
Each optional substitution is independently halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^aa , -N(R ^bb ) ₂ , -SH, -SR ^aa , -C(=O)R ^aa , -CO ₂ H, -CHO, -CO ₂ R ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -C(=O)N( R ^bb ) ₂ , -OC(=O)N(R ^bb ) ₂ , -NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , C _1-10 alkyl, and C _1-10 selected from perhaloalkyl;
R ^aa in each case is independently selected from C _1-10 alkyl, and C _1-10 perhaloalkyl;
R ^bb in any case is independently hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -P(=O)(R ^aa ) ₂ , selected from -P(=O)(OR ^cc ) ₂ , -P(=O)(N(R ^cc ) ₂ ) ₂ , C _1-10 alkyl, and C _1-10 perhaloalkyl;
R ^cc in each case is independently selected from hydrogen, C _1-10 alkyl, and C _1-10 perhaloalkyl;
Each nitrogen protecting group is independently benzyl (Bn), t-butyl carbonate (Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl , acetyl, or p-toluenesulfonamide (Ts); and each oxygen protecting group is independently selected from silyl, t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisopropyl selected from silyl (TIPS), triethylsilyl (TES), trimethylsilyl (TMS), methoxymethyl (MOM), tetrahydropyranyl (THP), t-butyl, benzyl (Bn), allyl, acetyl, pivaloyl, or benzoyl ,
Said compound. The compound has formula (I-d):
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof ; or the compound is of formula (If):
2. The compound according to claim 1 , which is represented by: or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. Formula (II-c):
A compound represented by, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in which:
R ¹ , R ² , R ³ , and R ⁴ in any case are independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted C _1-6 alkyl, optionally substituted C _1-6 is acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ;
Each occurrence of R ^a is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or an oxygen protecting group;
Each occurrence of R ^b is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or a nitrogen protecting group;
In each case R ^c is independently hydrogen, optionally substituted C _1-6 alkyl, or optionally substituted C _1-6 acyl;
m in each case is independently 0, 1, 2, 3, 4, or 5;
Each R ^N is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or a nitrogen protecting group;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
Each optional substitution is independently halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^aa , -N(R ^bb ) ₂ , -SH, -SR ^aa , -C(=O)R ^aa , -CO ₂ H, -CHO, -CO ₂ R ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -C(=O)N( R ^bb ) ₂ , -OC(=O)N(R ^bb ) ₂ , -NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , C _1-10 alkyl, and C _1-10 selected from perhaloalkyl;
R ^aa in each case is independently selected from C _1-10 alkyl, and C _1-10 perhaloalkyl;
R ^bb in any case is independently hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -P(=O)(R ^aa ) ₂ , selected from -P(=O)(OR ^cc ) ₂ , -P(=O)(N(R ^cc ) ₂ ) ₂ , C _1-10 alkyl, and C _1-10 perhaloalkyl;
R ^cc in each case is independently selected from hydrogen, C _1-10 alkyl, and C _1-10 perhaloalkyl;
Each nitrogen protecting group is independently benzyl (Bn), t-butyl carbonate (Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl , acetyl, or p-toluenesulfonamide (Ts); and each oxygen protecting group is independently selected from silyl, t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisopropyl selected from silyl (TIPS), triethylsilyl (TES), trimethylsilyl (TMS), methoxymethyl (MOM), tetrahydropyranyl (THP), t-butyl, benzyl (Bn), allyl, acetyl, pivaloyl, or benzoyl ,
the compound;
However, the compound has the formula
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. The compound has formula (II-d):
4. The compound according to claim 3, which is represented by: or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. Formula (III-b):
A compound represented by, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in which:
In each case, R ¹ , R ³ , and R ⁴ are independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ;
Each occurrence of R ^a is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or an oxygen protecting group;
Each occurrence of R ^b is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or a nitrogen protecting group;
In each case R ^c is independently hydrogen, optionally substituted C _1-6 alkyl, or optionally substituted C _1-6 acyl;
In any case, R ^5a is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or an oxygen protecting group;
m in each case is independently 0, 1, 2, 3, 4, or 5;
Each R ^N is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or a nitrogen protecting group;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
Each optional substitution is independently halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^aa , -N(R ^bb ) ₂ , -SH, -SR ^aa , -C(=O)R ^aa , -CO ₂ H, -CHO, -CO ₂ R ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -C(=O)N( R ^bb ) ₂ , -OC(=O)N(R ^bb ) ₂ , -NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , C _1-10 alkyl, and C _1-10 selected from perhaloalkyl;
R ^aa in each case is independently selected from C _1-10 alkyl, and C _1-10 perhaloalkyl;
R ^bb in any case is independently hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -P(=O)(R ^aa ) ₂ , selected from -P(=O)(OR ^cc ) ₂ , -P(=O)(N(R ^cc ) ₂ ) ₂ , C _1-10 alkyl, and C _1-10 perhaloalkyl;
R ^cc in each case is independently selected from hydrogen, C _1-10 alkyl, and C _1-10 perhaloalkyl;
Each nitrogen protecting group is independently benzyl (Bn), t-butyl carbonate (Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl , acetyl, or p-toluenesulfonamide (Ts); and each oxygen protecting group is independently selected from silyl, t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisopropyl selected from silyl (TIPS), triethylsilyl (TES), trimethylsilyl (TMS), methoxymethyl (MOM), tetrahydropyranyl (THP), t-butyl, benzyl (Bn), allyl, acetyl, pivaloyl, or benzoyl ,
Said compound. The compound has formula (III-c):
6. The compound according to claim 5, which is represented by: or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. Formula (IV-b):
A compound represented by, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in which:
R ¹ , R ² , R ³ , and R ⁴ in any case are independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted C _1-6 alkyl, optionally substituted C _1-6 is acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ;
Each occurrence of R ^a is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or an oxygen protecting group;
Each occurrence of R ^b is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or a nitrogen protecting group;
In each case R ^c is independently hydrogen, optionally substituted C _1-6 alkyl, or optionally substituted C _1-6 acyl;
m in each case is independently 0, 1, 2, 3, 4, or 5;
R ⁶ , R ⁷ , R ¹⁰ , and R ¹¹ in any case are independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted C _1-6 alkyl, optionally substituted C _1-6 is acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ;
R ⁹ is hydrogen, halogen, or optionally substituted C _1-6 alkyl;
R ⁸ is hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or an oxygen protecting group;
p is 0, 1, 2, or 3;
q is 0, 1, 2, 3, or 4;
Each R ^N is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or a nitrogen protecting group; and n is 0, 1, 2, 3, 4, 5, is 6, 7, 8, 9, or 10;
Each optional substitution is independently halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^aa , -N(R ^bb ) ₂ , -SH, -SR ^aa , -C(=O)R ^aa , -CO ₂ H, -CHO, -CO ₂ R ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -C(=O)N( R ^bb ) ₂ , -OC(=O)N(R ^bb ) ₂ , -NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , C _1-10 alkyl, and C _1-10 selected from perhaloalkyl;
R ^aa in each case is independently selected from C _1-10 alkyl, and C _1-10 perhaloalkyl;
R ^bb in any case is independently hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -P(=O)(R ^aa ) ₂ , selected from -P(=O)(OR ^cc ) ₂ , -P(=O)(N(R ^cc ) ₂ ) ₂ , C _1-10 alkyl, and C _1-10 perhaloalkyl;
R ^cc in each case is independently selected from hydrogen, C _1-10 alkyl, and C _1-10 perhaloalkyl;
Each nitrogen protecting group is independently benzyl (Bn), t-butyl carbonate (Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl , acetyl, or p-toluenesulfonamide (Ts); and each oxygen protecting group is independently selected from silyl, t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisopropyl selected from silyl (TIPS), triethylsilyl (TES), trimethylsilyl (TMS), methoxymethyl (MOM), tetrahydropyranyl (THP), t-butyl, benzyl (Bn), allyl, acetyl, pivaloyl, or benzoyl ,
Said compound. The compound has formula (IV-c):
8. The compound according to claim 7, which is represented by: or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. Formula (Vc):
A compound represented by, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in which:
In any case, R ¹ , R ³ , and R ⁴ are independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, - OR ^a , -N(R ^b ) ₂ , or -SR ^c ;
Each occurrence of R ^a is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or an oxygen protecting group;
Each occurrence of R ^b is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or a nitrogen protecting group;
In each case R ^c is independently hydrogen, optionally substituted C _1-6 alkyl, or optionally substituted C _1-6 acyl;
In any case, R ^5a is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or an oxygen protecting group;
m in each case is independently 0, 1, 2, 3, 4, or 5;
R ⁶ , R ⁷ , R ¹⁰ , and R ¹¹ in any case are independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted C _1-6 alkyl, optionally substituted C _1-6 is acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ;
R ⁹ is hydrogen, halogen, or optionally substituted C _1-6 alkyl;
R ⁸ is hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or an oxygen protecting group;
p is 0, 1, 2, or 3;
q is 0, 1, 2, 3, or 4;
Each R ^N is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or a nitrogen protecting group; and n is 0, 1, 2, 3, 4, 5, is 6, 7, 8, 9, or 10;
Each optional substitution is independently halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^aa , -N(R ^bb ) ₂ , -SH, -SR ^aa , -C(=O)R ^aa , -CO ₂ H, -CHO, -CO ₂ R ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -C(=O)N( R ^bb ) ₂ , -OC(=O)N(R ^bb ) ₂ , -NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , C _1-10 alkyl, and C _1-10 selected from perhaloalkyl;
R ^aa in each case is independently selected from C _1-10 alkyl, and C _1-10 perhaloalkyl;
R ^bb in any case is independently hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -P(=O)(R ^aa ) ₂ , selected from -P(=O)(OR ^cc ) ₂ , -P(=O)(N(R ^cc ) ₂ ) ₂ , C _1-10 alkyl, and C _1-10 perhaloalkyl;
R ^cc in each case is independently selected from hydrogen, C _1-10 alkyl, and C _1-10 perhaloalkyl;
Each nitrogen protecting group is independently benzyl (Bn), t-butyl carbonate (Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl , acetyl, or p-toluenesulfonamide (Ts); and each oxygen protecting group is independently selected from silyl, t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisopropyl selected from silyl (TIPS), triethylsilyl (TES), trimethylsilyl (TMS), methoxymethyl (MOM), tetrahydropyranyl (THP), t-butyl, benzyl (Bn), allyl, acetyl, pivaloyl, or benzoyl ,
Said compound. The compound has the formula (Vd):
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. Formula (VI-b):
A compound represented by, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in which:
R ⁶ , R ⁷ , R ¹⁰ , and R ¹¹ in any case are independently hydrogen, halogen, -CN, -NO ₂ , -N ₃ , optionally substituted C _1-6 alkyl, optionally substituted C _1-6 is acyl, -OR ^a , -N(R ^b ) ₂ , or -SR ^c ;
R ⁹ is hydrogen, halogen, or optionally substituted C _1-6 alkyl;
Each occurrence of R ^a is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or an oxygen protecting group;
Each occurrence of R ^b is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or a nitrogen protecting group;
In each case R ^c is independently hydrogen, optionally substituted C _1-6 alkyl, or optionally substituted C _1-6 acyl;
In any case, R ⁸ is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or an oxygen protecting group;
p is 0, 1, 2, or 3;
q is 0, 1, 2, 3, or 4;
Each R ^N is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or a nitrogen protecting group; and n is 0, 1, 2, 3, 4, 5, is 6, 7, 8, 9, or 10;
Each optional substitution is independently halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^aa , -N(R ^bb ) ₂ , -SH, -SR ^aa , -C(=O)R ^aa , -CO ₂ H, -CHO, -CO ₂ R ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -C(=O)N( R ^bb ) ₂ , -OC(=O)N(R ^bb ) ₂ , -NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , C _1-10 alkyl, and C _1-10 selected from perhaloalkyl;
R ^aa in each case is independently selected from C _1-10 alkyl, and C _1-10 perhaloalkyl;
R ^bb in any case is independently hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -P(=O)(R ^aa ) ₂ , selected from -P(=O)(OR ^cc ) ₂ , -P(=O)(N(R ^cc ) ₂ ) ₂ , C _1-10 alkyl, and C _1-10 perhaloalkyl;
R ^cc in each case is independently selected from hydrogen, C _1-10 alkyl, and C _1-10 perhaloalkyl;
Each nitrogen protecting group is independently benzyl (Bn), t-butyl carbonate (Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl , acetyl, or p-toluenesulfonamide (Ts); and each oxygen protecting group is independently selected from silyl, t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisopropyl selected from silyl (TIPS), triethylsilyl (TES), trimethylsilyl (TMS), methoxymethyl (MOM), tetrahydropyranyl (THP), t-butyl, benzyl (Bn), allyl, acetyl, pivaloyl, or benzoyl ,
Said compound. The compound has formula (VI-c):
12. The compound according to claim 11, which is represented by: or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R ¹ is optionally substituted C _1-6 alkyl;
Optionally, at least one occurrence of R ¹ is independently optionally substituted C _1-3 alkyl;
Optionally, at least one occurrence of R ¹ is independently unsubstituted C _1-3 alkyl; or Optionally, at least one occurrence of R ¹ is methyl;
A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R ² is optionally substituted C _1-6 alkyl;
Optionally, at least one occurrence of R ² is independently optionally substituted C _1-3 alkyl;
Optionally, at least one occurrence of R ² is independently unsubstituted C _1-3 alkyl; or Optionally, at least one occurrence of R ² is methyl;
A compound according to any one of claims 1 to 4, 7, 8 and 13, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. R ³ in at least one instance is optionally substituted C _1-6 alkyl;
Optionally, at least one occurrence of R ³ is optionally substituted C _1-3 alkyl;
Optionally, at least one occurrence of R ³ is unsubstituted C _1-3 alkyl; or Optionally, at least one occurrence of R ³ is methyl;
A compound according to any one of claims 1 to 10, 13 and 14, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. at least one occurrence of R ⁴ is independently halogen;
Optionally, at least one occurrence of R ⁴ is -Cl;
Optionally, at least one occurrence of R ⁴ is -CN;
Optionally, at least one case of m is 1;
Optionally, at least one instance of m is 1 and the point of attachment of R ⁴ to the benzenoid ring of the 1,4-diazepine ring is para;
A compound according to any one of claims 1 to 10 and 13 to 15, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. R ⁵ is -OR ^5a ;
Optionally, at least one occurrence of R ⁵ is independently -OR ^5a and at least one occurrence of R ^5a is independently optionally substituted C _1-6 alkyl;
Optionally, at least one occurrence of R ⁵ is independently -OR ^5a and at least one occurrence of R ^5a is independently optionally substituted C _1-3 alkyl;
Optionally, at least one occurrence of R ⁵ is independently -OR ^5a and at least one occurrence of R ^5a is independently unsubstituted C _1-3 alkyl;
Optionally, at least one occurrence of R ⁵ is independently -OCH ₃ ;
or,
Optionally, at least one occurrence of R ⁵ is independently -N(R ^5b ) ₂ and at least one occurrence of R ^5b is independently optionally substituted -C _1-6 alkyl- is heterocyclyl;
Optionally, at least one occurrence of R ⁵ is independently -N(R ^5b ) ₂ and at least one occurrence of R ^5b is independently optionally substituted -C _1-6 alkyl- is piperazinyl;
Optionally, in at least one case of R ⁵ the formula:
Represented by;
Optionally, at least one occurrence of R ⁵ is independently -N(R ^5b ) ₂ and at least one occurrence of R ^5b is independently optionally substituted C _1-6 alkyl. ;
Optionally, at least one occurrence of R ⁵ is independently -N(R ^5b ) ₂ and at least one occurrence of R ^5b is independently substituted C _1-3 alkyl; or optionally In the case of at least one of R ⁵ , the formula:
Represented by
A compound according to any one of claims 1 and 13 to 16, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. at least one occurrence of R ⁶ is independently optionally substituted C _1-6 alkyl;
Optionally, at least one occurrence of R ⁶ is independently optionally substituted C _1-3 alkyl;
Optionally, at least one occurrence of R ⁶ is independently unsubstituted C _1-3 alkyl; or Optionally, at least one occurrence of R ⁶ is methyl;
A compound according to any one of claims 7 to 17, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. at least one occurrence of R ⁷ is independently optionally substituted C _1-6 alkyl;
Optionally, at least one occurrence of R ⁷ is independently optionally substituted C _1-3 alkyl;
Optionally, at least one occurrence of R ⁷ is independently unsubstituted C _1-3 alkyl; or Optionally, at least one occurrence of R ⁷ is methyl;
A compound according to any one of claims 7 to 18, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. at least one occurrence of R ⁸ is independently optionally substituted C _1-6 alkyl;
Optionally, at least one occurrence of R ⁸ is independently optionally substituted C _1-3 alkyl;
Optionally, at least one occurrence of R ⁸ is independently unsubstituted C _1-3 alkyl; or Optionally, at least one occurrence of R ⁸ is methyl;
A compound according to any one of claims 7 to 19, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. at least one occurrence of R ⁹ is independently optionally substituted C _1-6 alkyl;
Optionally, at least one occurrence of R ⁹ is independently optionally substituted C _1-3 alkyl;
Optionally, at least one occurrence of R ⁹ is independently unsubstituted C _1-3 alkyl; or Optionally, at least one occurrence of R ⁹ is independently methyl;
A compound according to any one of claims 7 to 20, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. at least one occurrence of R ^N is hydrogen;
Optionally, in each case R ^N is hydrogen,
A compound according to any one of claims 2, 4, 6, 8, 10 and 12-21, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. The compound has formula (II-h):
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof;
A compound according to claim 3. n is 6, 7, or 8;
A compound according to any one of claims 2, 4, 6, 8, 10 and 12-23, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. or a pharmaceutically acceptable compound thereof according to any one of claims 2, 4, 6, 8, 10, and 12 to 23, wherein n is 1; or n is 7. obtained salts, stereoisomers, or tautomers. The formula below :
or
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof . Is the group consisting of:
or a pharmaceutically acceptable salt or tautomer thereof . The compound has the following formula:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
A compound according to claim 3. 29. A compound according to claim 28, selected from the group consisting of:
, or a pharmaceutically acceptable salt or tautomer thereof. The compound has the following formula:
or
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a tautomer thereof;
A compound according to claim 5. 31. The compound according to claim 30, selected from the group consisting of:
, or a pharmaceutically acceptable salt or tautomer thereof. The compound has the following formula:
or
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. 33. The compound according to claim 32, selected from the group consisting of:
, or a pharmaceutically acceptable salt or tautomer thereof. The compound has the following formula:
or
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
A compound according to claim 9. 35. The compound according to claim 34, selected from the group consisting of:
or a pharmaceutically acceptable salt or tautomer thereof. The compound has the following formula:
or
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
A compound according to claim 11. 37. The compound according to claim 36, selected from the group consisting of:
, or a pharmaceutically acceptable salt or tautomer thereof. The compound has the following formula (I-c):
The compound according to claim 1, or a pharmaceutically acceptable salt thereof. The compound has the following formula (II-c):
The compound according to claim 3, or a pharmaceutically acceptable salt thereof. The compound has the following formula (III -b ):
The compound according to claim 5, or a pharmaceutically acceptable salt thereof. The compound has the following formula (IV-b):
The compound according to claim 5, or a pharmaceutically acceptable salt thereof. The compound has the following formula (Vc):
The compound according to claim 9, or a pharmaceutically acceptable salt thereof. The compound has the following formula (VI-b):
The compound according to claim 11, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable excipient. thing. 45. A pharmaceutical composition according to claim 44 for use in the treatment of diseases associated with bromodomain-containing proteins . 45. A pharmaceutical composition according to claim 44 for use in a method for male contraception. 45. A pharmaceutical composition according to claim 44 for use in a method of inhibiting the activity of a bromodomain-containing protein in a subject or biological sample .